Prostaglandin ep4 receptor antagonist compounds

ABSTRACT

The disclosures herein relate to novel compounds of formula (1): (1) and salts thereof, wherein A, X, R 1 , R 2 , R 3 , R 4 , R 10  and R 11  are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with EP 4  receptors.

This application relates to novel compounds and their use asprostaglandin E₂ receptor 4 (EP₄) antagonists. Compounds describedherein may be useful in the treatment or prevention of diseases in whichEP₄ receptors are involved. The application is also directed topharmaceutical compositions comprising these compounds and themanufacture and use of these compounds and compositions in theprevention or treatment of such diseases in which EP₄ receptors areinvolved.

BACKGROUND OF THE INVENTION

Prostaglandins (PG) are small-molecule (˜400 Da) products produced bycyclooxygenases (COX; constitutively active COX1 and inducible COX2) andPG synthases, with a minor contribution from the isoprostane pathway,acting on arachidonic acid (AA). Prostaglandin E₂ (PGE₂) is the main COXproduct in myeloid and stromal cells whose levels are determined by thebalance between synthesis and 15-hydroxyprostaglandin dehydrogenase(15-PGDH)-mediated degradation. PGE₂ has 4 receptors (EP₁-EP₄) which arepresent on multiple cell types including macrophages, monocytes,platelets, sensory neurons, gastrointestinal tract, kidney, thymus,heart, lung, and uterus and drives a broad pharmacology mediatingnociception, aspects of neuronal signalling, haematopoiesis, regulationof blood flow, renal filtration and blood pressure, regulation ofmucosal integrity, vascular permeability, smooth muscle function andboth pro-inflammatory (vasodilation, recruitment and activation of mastcells, macrophages and neutrophils) and immunosuppressive immunefunction (detailed below). Functional PGE₂ antagonism has therapeuticpotential in a wide variety of disease settings, discussed below.

Abdominal aortic aneurysm (AAA). AAA is a life-threatening inflammatoryvascular disease associated with connective tissue degeneration, loss ofsmooth muscle leading to a dilated aorta which is prone to rupture.Diseased aortic tissue is associated with EP₄, PGE₂ expression andmacrophage and smooth muscle COX2 expression (Walton, L. J. et al.Circulation 100, 48-54 (1999)). EP₄ antagonism or gene deletion isassociated with beneficial outcomes in human and mouse preclinicalsystems (Yokoyama, U. et al. PLoS One 7, e36724 (2012)).

Ankylosing spondyltis (AS). AS is a heritable autoimmune diseaseassociated with HLA-B27 and EP₄. Inflammatory pain in rodent models canbe PGE₂ and EP₄ driven. AS patients' pain is NSAID responsive suggestingthat EP₄ antagonists may also be analgesic in AS with the long-termsafety benefits associated with specific EP₄ antagonism versus generalAA metabolism inhibition as discussed below in the cancer section(Murase, A. et al. Eur. J. Pharmacol. 580, 116-121 (2008)).

Alzheimer's disease (AD). Amyloid-β peptide (Aβ), generated by β- andγ-secretase-mediated proteolysis of β-amyloid precursor protein (APP),plays a key role AD pathogenesis. PGE₂ stimulates Aβ production throughendocytosis and activation of γ-secretase. Transgenic mice expressingmutant APP (APP23) crossed with EP₄-deficient mice have been shown toexhibit lower levels of Aβ plaque deposition and less neuronal andsynaptic loss than control mice. Oral treatment with a specific EP₄ hasbeen shown to improve cognitive performance and decrease Aβ levels inthe brain (Hoshino, T. et al. J. Neurochem. 120, 795-805 (2012)).

Atherosclerosis. EP₄ has been associated with destabilisation of humanatherosclerotic plaques via PGE₂-induction of MMP-2 and MMP-9(Cipollone, F. et al. Arteiosder. Thromb. Vasc. Biol. 25, 1925-31(2005)). EP₄ has also been validated as a target for prevention ofatherosclerosis development by analysis of EP₄-deficient macrophages,which had compromised survival, in a mouse model (Babaev, V. R. et al.Cell Metab. 8, 492-501 (2008)).

Cancer. Cancers or neoplasms are a leading cause of global mortality andmorbidity. Literature strongly supports a role for PGE₂ in epithelialcancers (GBD neoplasm categories of colon and rectum, lip and oralcavity, nasopharynx, other pharynx, gallbladder and biliary tract,pancreatic, non-melanoma skin, ovarian, testicular, kidney, bladder,thyroid, mesothelioma, esophageal, stomach, liver, larynx, tracheal,bronchus and lung, breast, cervical, uterine, prostate).

PGE₂ and associated receptors are upregulated in a wide variety ofepithelial neoplasms (colon, lip and oral cavity, gallbladder, pancreas,non-melanoma skin, ovarian, kidney, bladder, thyroid, mesothelioma,oesphageal squamous cell carcinoma, stomach, liver, squamous cell lungcarcinoma, breast, triple negative breast cancer, cervical, uterine,prostate cancer, head and neck squamous cell carcinoma) and expressionlevel correlates with disease progression (lip and oral cavity,oesphageal squamous cell carcinoma, cervical, prostate cancer, head andneck squamous cell carcinoma).

Celecoxib (COX-2-selective inhibitor) use was shown to decreaseincidence of adenoma development and rate of advanced adenomadevelopment but increase serious cardiovascular events in participantswho had an adenoma removed (Arber, N. et al. N. Engl. J. Med. 355,885-895 (2006)). Celecoxib has also been trialed as a co-treatment forvarious cancers. A meta-analysis of 5 randomised trials utilisingaspirin (COX-1 and COX-2 inhibitor) has demonstrated that doses of atleast 75 mg daily reduced the 20-year risk of colon cancer (Rothwell, P.M. et al. Lancet 376, 1741-1750 (2010)). PI3K mutations are present in15-20% of colorectal cancers (CRC) with many activating; PI3Kupregulation enhances PTGS2 (COX-2) activity and hence PGE₂ synthesis.Post-CRC diagnosis regular aspirin use was associated with a survivalbenefit in patients with mutated-, but not wild type-, PIK3CA (Liao, X.et al. N. Engl. J. Med. 367, 1596-1606 (2012)).

The therapeutic utility of COX inhibitors are limited by their potentialto cause either GI (NSAIDs e.g. aspirin) or CV (NSAIDs and Coxibs e.g.celecoxib) toxicity. Hence although the utility of aspirin and NSAIDs ingeneral in cancer chemoprevention has been recognised by internationalconsensus, the risk/benefit ratio remains challenging and so, definitiveuse recommendations have not been made. Taken together these datasuggest that broad spectrum suppression of prostaglandin synthesis istoo blunt a pharmacological tool to deliver appropriate benefit:riskbalance and there is a need for more specific medicines to be evaluated.We hence hypothesise that specific neutralisation of PGE₂ biologythrough EP₄ antagonism will deliver clinical benefit whilst minimisingthe side effect profile.

PGE₂ represents an attractive therapeutic target that drivesimmunosuppressive, immunological and oncological processes to facilitatecancer development and progression.

The COX-2 and epidermal growth factor receptor (EGFR) pathways areactivated in most human cancers. When human colorectal cancer (CRC)cells are transfected with COX2 they proliferate in association withEGFR induction suggesting crosstalk between the pathways. Mice bearingCRC tumours have shown reduced tumour growth when administeredPGE₂-neutralising antibody (Stolina, M. et al. J. Immunol. 164, 361-70(2000)). PGE₂ is generally anti-apoptotic in hypoxic and treatment (suchas radiotherapy) conditions, and activates the Ras-MAPK/ERK and PI3K/AKTsurvival pathways (Wang, D. & Dubois, R. N. Gut 55, 115-22 (2006)).Preclinical rodent and human studies support the view that PGE₂ plays akey role in cancer development and progression and have started toelucidate the mechanism. COX expression in tumours generates PGE2 whichsubverts myeloid function; COX ablation with knockouts or aspirin/coxibenables immune control of the tumour and COX inhibition synergises withimmune checkpoint blockade in the form of PD1-blocking antibody (Zelaneyet al., Cell, 2015). These data suggest that other known immunecheckpoint blocking agents may synergise with PGE2 suppression. Finallythe COX inflammatory signature is conserved across mouse and humancancer biopsies (Zelaney et al., Cell, 2015). It is highly likely thatdoses of coxibs required to fully suppress PGE2 in the tumourmicroenvironment exceed those licensed for clinical use in peoplefurther supporting the need for a drug to block the cancer-supportingbiology of PGE2 without generating dose-limiting toxicities.

Multiple immune cells bear adenosine receptors (primarily A2_(A) andA2_(b)) which, in common with EP₂ and EP₄, act to increase intracellularcAMP and mediate immunosuppression. PGE2 and adenosine are co-expressedin neoplasms supporting the concept that clinical benefit will accrue bycombining PGE2 and adenosine pathway modulators.

These findings suggest that functional antagonism of PGE₂ has strongpotential to both deliver strong clinical benefit to patients withvarious epithelial cancers but also to synergise with current standardof care and new IO agents in development.

Diabetic nephropathy. Diabetes mellitus is associated with multiplemacrovascular complications including nephropathy, retinopathy andneuropathy. Diabetic nephropathy is the leading cause of end-stage renaldisease, associated with high cardiovascular risk and is a commonsequelae for approximately ⅓^(rd) of diabetes mellitus patients. Currenttherapy centres on control of blood glucose and blood pressure, tominimise the key risk factors of hyperglycaemia, hypertension,dyslipidemia, obesity, but is insufficiently efficacious. PGE₂ is themost abundant renal prostaglandin and plays a variety of roles in renalphysiology; inflammation, volume homeostasis, regulation of salt andwater balance, renal blood flow, renin release, glomerular haemodynamics(Breyer, M. D., Jacobson, H. R. & Breyer, R. M. J. Am. Soc. Nephrol. 7,8-17 (1996)); EP₁ and EP₃ are generally vasoconstrictive whereas EP₂ andEP₄ mediate vasodilation. EP₄ has been implicated in mediating renaldamage in preclinical models mimicking aspects of diabetic nephropathy.Four weeks repeated oral administration of the EP₄ antagonist ASP7657has been shown to dose-dependently attenuate albuminuria in type 2diabetic db/db mice (Mizukami, K. et al. Naunyn. Schmiedebergs. Arch.Pharmacol. 391, 1319-1326 (2018)).

Endometriosis. Endometriosis is characterised by persistent colonisationof endometrial tissue outside the uterine cavity, likely via retrogrademenstruation, leading to typical foci and the formation of“endometriotic lesions” which have upregulated COX2 and elevated PGE₂.

PGE₂ stimulates integrin-mediated adhesion of endometriotic epithelialand stromal cells and drives proliferation of endometriotic epithelialcells and stromal cells via EP₂ and EP₄; when PGE₂ is blocked thisdrives cells into apoptosis. Data suggest that EP₄ antagonism may be oftherapeutic utility in endometriosis (Lee, J., Banu, S. K., Burghardt,R. C., Starzinski-Powitz, A. & Arosh, J. A. Biol. Reprod. 88, 77(2013)).

Inflammatory bowel disease. PGE2 directly promotes differentiation andproinflammatory functions of IL-17-producing T helper (Th17) cells(Boniface et al, JEM, 2009) via upregulation of IL-23 receptors (Lee etal., JACI, 2019) which have been implicated in driving IBD; the IL-12/23neutralising ustekinumab is efficacious in ulcerative colitis andcrohn's disease.

Migraine. PGE₂ has strong target validation in migraine. PGE₂ isupregulated in jugular blood, plasma and saliva of people experiencingmigraine. IV infusion of prostaglandins can trigger migraine-symptoms inmigraine patients; PGE₂ relaxes human cerebral arteries in anEP₄-dependent fashion (Maubach, K. A. K. A. et al. Br. J. Pharmacol.156, 316-327 (2009)). In vitro and in vivo chemical stimulation of dura,trigeminal neurons, afferent nerves and sensory afferents causes PGE₂release. PGE₂ induces augmentation of peptide release and sensitizationof sensory neurons via EP₄ (Southall, M. D. & Vasko, M. R. J. Biol.Chem. 276, 16083-91 (2001)). These data suggest that EP₄ antagonists mayhave therapeutic utility in the treatment of migraine.

Multiple sclerosis (MS). PGE₂ levels are dearly detectable in MScerebrospinal fluid (CSF) but not CSF from people without neurologicaldisease. Functional PGE₂ antagonists are predicted to provide clinicalbenefit in MS via inhibition of IL-23 production and suppression of Th1and Th17 cell development (Cua, D. J. et al. Nature 421, 744-8 (2003)).

Osteoarthritis (OA). PGE₂ is upregulated in synovial fluid and cartilagefrom OA patients and PGE₂ stimulates matrix degradation on OAchondrocytes via EP₄ (Attur, M. et al. J. Immunol. 181, 5082-8 (2008)).

Osteoporosis. PGE₂ plays a key role in driving bone resorption,primarily through EP₄. Bone loss is often seen when tumours metastasiseto bone; preclinical data from a breast metastasis model shows that EP₄antagonism reduces loss of bone mineral density (Takita, M., Inada, M.,Maruyama, T. & Miyaura, C. FEBS Lett. 581, 565-571 (2007)).

Overactive bladder. Cyclophosphamide injection induces an overactivebladder in rats. EP₄ antagonist given concurrently, systemically ordirectly into bladder tissue, has been shown to reduce bladderinflammation and frequency of bladder contraction (overactivity)(Chuang, Y.-C., Tyagi, P., Huang, C.-C., Chancellor, M. B. & Yoshimura,N. BJU Int. 110, 1558-1564 (2012)).

Rheumatoid arthritis. PGE₂ can act as both an immunosuppressant and animmunostimulant and perhaps should be considered a context-dependentimmunomodulator. EP₄-deficient, versus WT or EP₁₋₃-deficient, mice havebeen shown to develop reduced arthritis symptom in a CAIA model clearlyimplicating EP₄ (McCoy, J. M., Wicks, J. R. & Audoly, L. P. J. Clin.Invest. 110, 651-658 (2002)).

Data suggest that functional antagonism of PGE₂ has the potential toameliorate the clinically-relevant Th17 axis in rheumatoid arthritis andhence provide strong clinical benefit.

The invention described herein relates to novel compounds and their useas EP₄ antagonists. Compounds described herein may be useful in thetreatment or prevention of diseases in which EP₄ receptors are involved.The invention is also directed to pharmaceutical compositions comprisingthese compounds and the manufacture and use of these compounds andcompositions in the prevention or treatment of such diseases in whichEP₄ receptors are involved. Thus the compounds of the invention may beuseful in the treatment of Abdominal aortic aneurysm (AAA), Ankylosingspondylitis (AS), Alzheimer's disease (AD), Atherosclerosis, Cancerincluding epithelial cancers (GBD neoplasm categories of colon andrectum, lip and oral cavity, nasopharynx, other pharynx, gallbladder andbiliary tract, pancreatic, non-melanoma skin, ovarian, testicular,kidney, bladder, thyroid, mesothelioma, esophageal, stomach, liver,larynx, tracheal, bronchus and lung, breast, cervical, uterine,prostate), Diabetic nephropathy, Endometriosis, Inflammatory boweldisease, Migraine, Multiple sclerosis (MS), Osteoarthritis (OA) andRheumatoid arthritis.

Compounds of the invention may be used as single therapeutics or incombinations with one or more other therapeutics of any type. For thetreatment or prevention of cancer this may include radiotherapy and/orchemotherapy and/or immunotherapy and/or other oncology modulators.

THE INVENTION

The present invention provides compounds having activity asprostaglandin E₂ receptor 4 (EP₄) antagonists.

The invention provides a compound of Formula (1):

or a salt thereof, wherein;

A is selected from the group consisting of:

X is an optionally substituted phenyl ring, an optionally substitutedpyridyl ring or an optionally substituted imidazopyridine ring system;

R¹ and R² are independently H or a C₁₋₃ alkyl group which is optionallysubstituted with one or more fluorine atoms; or R¹ and R² are joined toform a 3-6 membered carbocyclic ring which is optionally substitutedwith one or more fluorine atoms;

R³ is H, C₁₋₃ alkyl or F;

R⁴ is H or C₁₋₃ alkyl;

R⁸ is C₁₋₃ alkyl or a C₃₋₆ cycloalkyl ring;

and either R¹⁰ and R¹¹ are both methyl or R¹⁰ and R¹¹ are joined to forma cyclobutyl ring.

The compounds may be used as EP₄ receptor antagonists. The compounds maybe used in the manufacture of medicaments. The compounds or medicamentsmay be for use in treating, preventing, ameliorating, controlling orreducing the risk of diseases or disorders in which EP₄ receptors areinvolved. Thus the compounds of the invention may be useful in thetreatment of Abdominal aortic aneurysm (AAA), Ankylosing spondylitis(AS), Alzheimer's disease (AD), Atherosclerosis, Cancer includingepithelial cancers (GBD neoplasm categories of colon and rectum, lip andoral cavity, nasopharynx, other pharynx, gallbladder and biliary tract,pancreatic, non-melanoma skin, ovarian, testicular, kidney, bladder,thyroid, mesothelioma, esophageal, stomach, liver, larynx, tracheal,bronchus and lung, breast, cervical, uterine, prostate), Diabeticnephropathy, Endometriosis, Inflammatory bowel disease, Migraine,Multiple sclerosis (MS), Osteoarthritis (OA) and Rheumatoid arthritis.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to novel compounds. The invention also relates tothe use of novel compounds as antagonists of the EP₄ receptor. Theinvention further relates to the use of novel compounds in themanufacture of medicaments for use as EP₄ receptor antagonists.

The invention further relates to compounds, compositions and medicamentsfor the treatment of Abdominal aortic aneurysm (AAA), Ankylosingspondylitis (AS), Alzheimer's disease (AD), Atherosclerosis, Cancerincluding epithelial cancers (GBD neoplasm categories of colon andrectum, lip and oral cavity, nasopharynx, other pharynx, gallbladder andbiliary tract, pancreatic, non-melanoma skin, ovarian, testicular,kidney, bladder, thyroid, mesothelioma, esophageal, stomach, liver,larynx, tracheal, bronchus and lung, breast, cervical, uterine,prostate), Diabetic nephropathy, Endometriosis, Inflammatory boweldisease, Migraine, Multiple sclerosis (MS), Osteoarthritis (OA) andRheumatoid arthritis.

The invention provides a compound of Formula (1):

or a salt thereof, wherein;

A is selected from the group consisting of:

X is an optionally substituted phenyl ring, an optionally substitutedpyridyl ring or an optionally substituted imidazopyridine ring system;

R¹ and R² are independently H or a C₁₋₃ alkyl group which is optionallysubstituted with one or more fluorine atoms; or R¹ and R² are joined toform a 3-6 membered carbocyclic ring which is optionally substitutedwith one or more fluorine atoms;

R³ is H, C₁₋₃ alkyl or F;

R⁴ is H or C₁₋₃ alkyl;

R⁸ is C₁₋₃ alkyl or a C₃₋₆ cycloalkyl ring;

and either R¹⁰ and R¹¹ are both methyl or R¹⁰ and R¹¹ are joined to forma cyclobutyl ring.

Also provided is a compound of Formula (1a):

or a salt thereof, wherein;

A is selected from the group consisting of:

X is an optionally substituted phenyl ring, an optionally substitutedpyridyl ring or an optionally substituted imidazopyridine ring system;

R¹ and R² are independently H or a C₁₋₃ alkyl group which is optionallysubstituted with one or more fluorine atoms; or R¹ and R² are joined toform a 3-6 membered carbocyclic ring which is optionally substitutedwith one or more fluorine atoms;

R³ is H, C₁₋₃ alkyl or F;

R⁴ is H or C₁₋₃ alkyl;

and R⁸ is C₁₋₃ alkyl or a C₃₋₆ cycloalkyl ring.

Also provided is a compound of Formula (1b):

or a salt thereof, wherein;

A is selected from the group consisting of:

X is an optionally substituted phenyl ring, an optionally substitutedpyridyl ring or an optionally substituted imidazopyridine ring system;

R¹ and R² are independently H or a C₁₋₃ alkyl group which is optionallysubstituted with one or more fluorine atoms; or R¹ and R² are joined toform a 3-6 membered carbocyclic ring which is optionally substitutedwith one or more fluorine atoms;

R³ is H, C₁₋₃ alkyl or F;

R⁴ is H or C₁₋₃ alkyl;

and R⁸ is C₁₋₃ alkyl or a C₃₋₆ cycloalkyl ring.

The invention provides a compound of Formula (1c):

or a salt thereof, wherein:

A is selected from the group consisting of:

X is an optionally substituted phenyl ring, an optionally substitutedpyridyl ring or an optionally substituted imidazopyridine ring system;

R¹ and R² are independently H or a C₁₋₃ alkyl group which is optionallysubstituted with one or more fluorine atoms; or R¹ and R² are joined toform a 3-6 membered carbocyclic ring which is optionally substitutedwith one or more fluorine atoms;

R⁴ is H or C₁₋₃ alkyl;

R⁸ is C₁₋₃ alkyl or a C₃₋₆ cycloalkyl ring;

and either R¹⁰ and R¹¹ are both methyl or R¹⁰ and R¹¹ are joined to forma cyclobutyl ring.

Particular compounds include compounds of Formula (2) and (2i):

or a salt thereof, wherein;

A, R¹, R², R³ and R⁴ are as defined above;

Q, W and T are CH or N;

Z and Y are C or N;

where either one or none of Q, W, T, Y and Z is N, R⁵ is absent if Y isN and R⁶ is absent if Z is N;

R⁵ and R⁶ are independently selected from H, halo, CN, OH, SF₅, C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₁₋₅ alkoxy, OR⁷ and SO₂R⁷, wherein the alkyl,cycloalkyl and alkoxy groups are optionally substituted with one or morefluorine atoms and any one atom of the alkyl or cycloalkyl group may beoptionally replaced by a heteroatom selected from O, S and N; or R⁵ andR⁶ are joined to form a 5 or 6-membered carbocyclic or heterocyclic ringwhich is optionally substituted with one or more fluorine atoms; and R⁷is a C₁₋₆ alkyl group which is optionally substituted with one or morefluorine atoms or a C₃₋₆ cycloalkyl group which is optionallysubstituted with one or more fluorine atoms.

Particular compounds include compounds of Formula (2a) and (2b):

and salts thereof, wherein A, T, Y, Z, Q, W, R¹, R², R⁵ and R⁶ are asdefined above.

Particular compounds include compounds of Formula (2ia) and (2ib):

and salts thereof, wherein A, T, Y, Z, Q, W, R¹, R², R⁵ and R⁶ are asdefined above.

Particular compounds include compounds of Formula (3), (3a), (3b), (3i),(3ia), (3ib):

and salts thereof, wherein A, T, Y, Z, Q, W, R¹, R², R³, R⁴, R⁵ and R⁶are as defined above.

Particular compounds include compounds of Formula (4), (4a), (4b), (4i),(4ia) and (4ib):

and salts thereof, wherein A, T, Y, Z, Q, W, R³, R⁴, R⁵ and R⁶ are asdefined above.

Particular compounds include compounds of Formula (5), (5a), (5b), (5i),(5ia) and (5ib):

and salts thereof, wherein A, T, Y, Z, Q, W, R³, R⁴, R⁵ and R⁶ are asdefined above.

Particular compounds include compounds of Formula (6), (6a), (6b), (6c),(6d), (6e), (6f), (6g), (6h), (6j), (6k) and (6l):

and salts thereof, wherein A, R¹, R², R³, R⁴, R⁵ and R⁶ are as definedabove.

Particular compounds include compounds of Formula (6i), (6ia), (6ib),(6ic), (6id), (6ie), (6if), (6ig), (6ih), (6ij), (6ik) and (6il):

and salts thereof, wherein A, R¹, R², R³, R⁴, R⁵ and R⁶ are as definedabove.

The compound can be a compound of Formula (7):

and salts thereof, wherein X, R¹, R², R³, R⁴, R¹⁰ and R¹¹ are as definedabove.

In the compounds herein, A can be selected from:

In the compounds herein, A can be selected from the group consisting of:CO₂H, tetrazole, 1,2,4-oxadiazol-5(2H)-one, 1,3,4-oxadiazol-2(3H)-one,CONHSO₂R⁸, CONHSO₂Me, SO₃H, 1,3,4-oxadiazole-2(3H)-thione,1,2,4-oxadiazole-5(2H)-thione, 1,2,4-thiadiazol-5(2H)-one,1,2,5-thiadiazolidin-3-one 1,1-dioxide and 2,4-oxazolidinedione.

In the compounds herein, A can be selected from CO₂H, CONHSO₂Me and atetrazole ring. A can be CO₂H. A can be CONHSO₂Me. A can be a tetrazolering.

In the compounds herein, R¹ and R² can independently be H or a C₁₋₃alkyl group which is optionally substituted with one or more fluorineatoms. R¹ and R² can be joined to form a 3-6 membered carbocyclic ringwhich is optionally substituted with one or more fluorine atoms.

In the compounds herein, R¹ can be H. R¹ can be a C₁₋₃ alkyl group whichis optionally substituted with one or more fluorine atoms. R¹ can bejoined to R² to form a 3-6 membered carbocyclic ring which is optionallysubstituted with one or more fluorine atoms. R¹ can be joined to R² toform a 3-6 membered carbocyclic ring. R¹ can be a C₁₋₃ alkyl groupoptionally substituted with 1-3 fluorine atoms. R¹ can be a C₁₋₃ alkylgroup. R¹ can be methyl. R¹ can be joined to R² to form a cyclopropylring.

In the compounds herein, R² can be H. R² can be a C₁₋₃ alkyl group whichis optionally substituted with one or more fluorine atoms. R² can bejoined to R¹ to form a 3-6 membered carbocyclic ring which is optionallysubstituted with one or more fluorine atoms. R² can be joined to R¹ toform a 3-6 membered carbocyclic ring. R² can be a C₁₋₃ alkyl groupoptionally substituted with 1-3 fluorine atoms. R² can be a C₁₋₃ alkylgroup. R² can be methyl. R² can be joined to R¹ to form a cyclopropylring.

In the compounds herein, R¹ can be methyl and R² can be H. R¹ and R² canboth be methyl. R¹ and R² can both be H. R¹ and R² can be joined to forma cyclopropyl ring.

In the compounds herein R³ can be H, C₁₋₃ alkyl or F. R³ can be H,methyl or F. R³ can be C₁₋₃ alkyl. R³ can be methyl. R³ can be H. R³ canbe F.

In the compounds herein R⁴ can be H or C₁₋₃ alkyl. R⁴ can be H ormethyl. R⁴ can be C₁₋₃ alkyl. R⁴ can be methyl. R⁴ can be H.

In the compounds herein X can be an optionally substituted phenyl ring.X can be an optionally substituted pyridyl ring. X can be an optionallysubstituted imidazopyridine ring system.

In the compounds herein, X can be any of the following ring systems,which may be optionally substituted:

In the compounds herein, X can be:

wherein T, Y, Z, Q, W, R⁵ and R⁶ are as defined above.

In the compounds herein, X can be selected from the group consisting of:

wherein R⁵ and R⁶ are as defined herein.

In the compounds herein, R⁵ and R⁶ can be independently selected from H,halo, CN, OH, SF₅, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, OR⁷ andSO₂R⁷, wherein the alkyl, cycloalkyl and alkoxy groups are optionallysubstituted with one or more fluorine atoms and any one atom of thealkyl or cycloalkyl group may be optionally replaced by a heteroatomselected from 0, S and N. R⁵ and R⁶ can be joined to form a 5 or6-membered carbocyclic or heterocyclic ring which is optionallysubstituted with one or more fluorine atoms. R⁵ and R⁶ can beindependently selected from H, Cl, F, CN, OH, SO₂Me, SO₂Et,SO₂-cyclopropyl, SF₅, CF₃, CF₂H, OMe OCF₃, OCF₂H, CH₂OH, CH₂OMe,cyclopropyl and oxetanyl.

In the compounds herein, R⁵ can be selected from H, halo, CN, OH, SF₅,OR⁷ and SO₂R⁷. R⁵ can be C₁₋₆ alkyl, C₁₋₆ alkoxy or C₃₋₆ cycloalkyl,wherein the alkyl, cycloalkyl and alkoxy groups are optionallysubstituted with one or more fluorine atoms and any one atom of thealkyl or cycloalkyl group may be optionally replaced by a heteroatomselected from O, S and N. R⁵ can be C₁₋₆ alkyl, C₁₋₆ alkoxy or C₃₋₆cycloalkyl, wherein the alkyl, cycloalkyl and alkoxy groups areoptionally substituted with one or more fluorine atoms. R⁵ can be C₁₋₆alkyl, C₁₋₆ alkoxy or C₃₋₆ cycloalkyl. R⁵ can be selected from H, C, F,CN, OH, SO₂Me, SO₂Et, SO₂-cyclopropyl, SF₅, CF₃, CF₂H, OMe OCF₃, OCF₂H,CH₂OH, CH₂OMe, cyclopropyl and oxetanyl. R⁵ can be H. R⁵ can be CF₃ orF. R⁵ can be CF₃. R⁵ can be F. R⁵ can be joined to R⁶ to form a 5 or6-membered carbocyclic or heterocyclic ring which is optionallysubstituted with one or more fluorine atoms. R⁵ can be joined to R⁶ toform a fused dioxolane ring which is optionally substituted with one ortwo fluorine atoms. R⁵ can be joined to R⁶ to form a fused dioxolanering. R⁵ can be joined to R⁶ to form a fused dioxolane ring substitutedwith one or two fluorine atoms. R⁵ can be joined to R⁶ to form a fuseddioxolane ring substituted with two fluorine atoms. R⁵ and R⁶ can bejoined to form a fused imidazole ring. R⁵ and R⁶ can be joined to forman imidazo[1,2-a]pyridine ring system together with the ring to whichthey are attached.

In the compounds herein, R⁶ can be selected from H, halo, CN, OH, SF₅,OR⁷ and SO₂R⁷. R⁶ can be C₁₋₆ alkyl, C₁₋₆ alkoxy or C₃₋₆ cycloalkyl,wherein the alkyl, cycloalkyl and alkoxy groups are optionallysubstituted with one or more fluorine atoms and any one atom of thealkyl or cycloalkyl group may be optionally replaced by a heteroatomselected from O, S and N. R⁶ can be C₁₋₆ alkyl, C₁₋₆ alkoxy or C₃₋₆cycloalkyl, wherein the alkyl, cycloalkyl and alkoxy groups areoptionally substituted with one or more fluorine atoms. R⁶ can be C₁₋₆alkyl, C₁₋₆ alkoxy or C₃₋₆ cycloalkyl. R⁶ can be selected from H, Cl, F,CN, OH, SO₂Me, SO₂Et, SO₂-cyclopropyl, SF₅, CF₃, CF₂H, OMe OCF₃, OCF₂H,CH₂OH, CH₂OMe, cyclopropyl and oxetanyl. R⁶ can be H. R⁶ can be CF₃ orF. R⁶ can be CF₃. R⁶ can be F. R⁶ can be joined to R⁵ to form a 5 or6-membered carbocyclic or heterocyclic ring which is optionallysubstituted with one or more fluorine atoms. R⁶ can be joined to R⁵ toform a fused dioxolane ring which is optionally substituted with one ortwo fluorine atoms. R⁶ can be joined to R⁵ to form a fused dioxolanering. R⁶ can be joined to R⁵ to form a fused dioxolane ring substitutedwith one or two fluorine atoms. R⁶ can be joined to R⁵ to form a fuseddioxolane ring substituted with two fluorine atoms. R⁶ and R⁵ can bejoined to form a fused imidazole ring. R⁶ and R⁵ can be joined to forman imidazo[1,2-a]pyridine ring system together with the ring to whichthey are attached.

In the compounds herein, Q, W and T can be CH or N. Z and Y can be C orN.

In the compounds herein, either one or none of Q, W, T, Y and Z is N. R⁵is absent if Y is N. R⁶ is absent if Z is N.

In the compounds herein, Q, W and T can be CH and Z and Y can be C. Q, Wand T can be CH, Z can be C and Y can be N. Q, W and T can be CH, Z canbe N and Y can be C. Q and W can be CH, T can be N and Z and Y can be C.Q and T can be CH, W can be N and Z and Y can be C. T and W can be CH, Qcan be N and Z and Y can be C.

In the compounds herein, R⁷ can be a C₁₋₆ alkyl group which isoptionally substituted with one or more fluorine atoms. R⁷ can be a C₃₋₆cycloalkyl group which is optionally substituted with one or morefluorine atoms. R⁷ can be a C₁₋₆ alkyl group. R⁷ can be a C₃₋₆cycloalkyl group. R⁷ can be methyl. R⁷ can be ethyl. R⁷ can be CF₃. R⁷can be CF₂H.

In the compounds herein R⁸ can be C₁₋₃ alkyl. R⁸ can be C₃₋₆ cycloalkyl.R⁸ can be methyl.

In the compounds herein, R¹⁰ and R¹¹ can both be methyl or R¹⁰ and R¹¹can be joined to form a cyclobutyl ring. R¹⁰ can be methyl or joined toR¹¹ form a cyclobutyl ring. R¹¹ can be methyl or joined to R¹⁰ form acyclobutyl ring.

The compound can be selected from any one of Examples 1 to 101, shown inTable 1, or a salt thereof.

The compound can be selected from the group consisting of:

-   4-((S)-1-((R)-3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)ethyl)benzoic    acid;-   (R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)cyclopropyl)benzoic    acid;-   4-((1S)-1-(2-((3-methoxybenzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((S)-2-((4-fluorobenzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-2-((4-fluorobenzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((1S)-1-(2-((4-methoxybenzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((S)-3-methyl-2-((3-(methylsulfonyl)benzyl)oxy)butanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-3-methyl-2-((3-(methylsulfonyl)benzyl)oxy)butanamido)ethyl)benzoic    acid;-   4-((S)-1-((S)-3-methyl-2-((4-(methylsulfonyl)benzyl)oxy)butanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-3-methyl-2-((4-(methylsulfonyl)benzyl)oxy)butanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-2-((4-chlorobenzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-2-((3-chlorobenzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-2-((4-(difluoromethyl)benzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-2-((3-(difluoromethyl)benzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-3-methyl-2-((3-(trifluoromethyl)benzyl)oxy)butanamido)ethyl)benzoic    acid;-   4-((S)-1-((S)-3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)ethyl)benzoic    acid;-   4-((1S)-1-(2-((3-fluorobenzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-2-(benzyloxy)-3-methylbutanamido)ethyl)benzoic acid;-   4-((S)-1-((R)-3-methyl-2-((3-(trifluoromethoxy)benzyl)oxy)butanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-2-((4-cyanobenzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-2-((3-cyanobenzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-2-((4-(difluoromethoxy)benzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-2-((3-(difluoromethoxy)benzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-3-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)methoxy)butanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-3-methyl-2-((4-(pentafluoro-λ⁶-sulfaneyl)benzyl)oxy)butanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-2-((3,4-difluorobenzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methoxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-2-((4-(difluoromethyl)-3-fluorobenzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-2-((4-cyclopropylbenzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   (R)-4-(1-(2-((4-fluorobenzyl)oxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   4-((S)-1-((R)-2-((3-(difluoromethoxy)-4-fluorobenzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   (R)-4-(1-(3-methyl-2-((3-(methylsulfonyl)benzyl)oxy)butanamido)cyclopropyl)benzoic    acid;-   4-((S)-1-((R)-2-((5-(difluoromethyl)pyridin-2-yl)methoxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-2-((4-fluoro-3-(methylsulfonyl)benzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   2-methyl-4-((S)-1-((R)-3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)ethyl)benzoic    acid;-   (R)-4-(1-(2-((3,4-difluorobenzyl)oxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   4-((S)-1-((R)-2-((3-hydroxybenzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-2-((3-cyclopropylbenzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-2-((3-(methoxymethyl)benzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-2-((4-hydroxybenzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   (R)—N—((S)-1-(4-(1H-tetrazol-5-yl)phenyl)ethyl)-2-((4-fluorobenzyl)oxy)-3-methylbutanamide;-   (R)—N—((S)-1-(4-(1H-tetrazol-5-yl)phenyl)ethyl)-3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamide;-   4-((S)-1-((R)-2-((3-(ethylsulfonyl)benzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((S)-1-((R)-2-((3-(hydroxymethyl)benzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((1    S)-1-((2R)-2-(1-(4-fluorophenyl)ethoxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-((1    S)-1-(3-methyl-2-((4-(oxetan-3-yl)benzyl)oxy)butanamido)ethyl)benzoic    acid;-   4-((1    S)-1-(3-methyl-2-((3-(oxetan-3-yl)benzyl)oxy)butanamido)ethyl)benzoic    acid;-   (R)-4-(1-(2-((3-chlorobenzyl)oxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   4-((1S)-1-((2R)-3-methyl-2-(1-(4-(trifluoromethyl)phenyl)ethoxy)butanamido)ethyl)benzoic    acid;-   (R)-4-(1-(2-((3-(difluoromethoxy)benzyl)oxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   4-((S)-1-((R)-3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)ethyl)-N-(methylsulfonyl)benzamide;-   (R)-4-(1-(2-((3-cyanobenzyl)oxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   (R)-4-(1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methoxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   (R)-4-(1-(2-((3-(ethylsulfonyl)benzyl)oxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   (R)-4-(1-(2-((3-(difluoromethoxy)-4-fluorobenzyl)oxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   (R)-4-(1-(3-methyl-2-((3-(trifluoromethoxy)benzyl)oxy)butanamido)cyclopropyl)benzoic    acid;-   (R)-4-((3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)methyl)benzoic    acid;-   (R)-4-(1-(2-((3-(methoxymethyl)benzyl)oxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   (R)-4-(1-(2-((4-(difluoromethyl)-3-fluorobenzyl)oxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   (R)-4-(1-(2-((4-(difluoromethyl)benzyl)oxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   (R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)cyclopropyl)-N-(methylsulfonyl)benzamide;-   (R)-4-(2-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)propan-2-yl)benzoic    acid;-   (R)-4-(1-(2-((3-cyclopropylbenzyl)oxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   4-((S)-1-((R)-2-(imidazo[1,2-a]pyridin-7-ylmethoxy)-3-methylbutanamido)ethyl)benzoic    acid;-   (R)-4-(1-(2-((2-(difluoromethoxy)pyridin-4-yl)methoxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   (R)-4-(1-(2-((4-(difluoromethoxy)pyridin-2-yl)methoxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   (R)—N-(1-(4-(1H-tetrazol-5-yl)phenyl)cyclopropyl)-3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamide;-   (R)—N-(1-(4-(1H-tetrazol-5-yl)phenyl)cyclopropyl)-2-((4-fluorobenzyl)oxy)-3-methylbutanamide;-   (R)—N-(1-(4-(1H-tetrazol-5-yl)phenyl)cyclopropyl)-2-((3,4-difluorobenzyl)oxy)-3-methylbutanamide;-   (R)—N-(1-(4-(1H-tetrazol-5-yl)phenyl)cyclopropyl)-2-((3-(difluoromethoxy)benzyl)oxy)-3-methylbutanamide;-   (R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)cyclobutyl)benzoic    acid;-   4-((S)-1-((R)-2-((2-(difluoromethoxy)pyridin-4-yl)methoxy)-3-methylbutanamido)ethyl)benzoic    acid;-   (R)-4-(1-(3-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)methoxy)butanamido)cyclopropyl)benzoic    acid;-   (R)-4-(1-(3-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methoxy)butanamido)cyclopropyl)benzoic    acid;-   4-((S)-1-((R)-2-((4-(difluoromethoxy)pyridin-2-yl)methoxy)-3-methylbutanamido)ethyl)benzoic    acid;-   (R)-4-(1-(2-((3-chloro-4-fluorobenzyl)oxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   4-(1-((2R)-2-((4-chloro-5-fluorocyclohexa-1,3-dien-1-yl)methoxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   (R)-2-((3-cyclopropylbenzyl)oxy)-N-(1-(4-(2,3-dihydro-1H-tetrazol-5-yl)phenyl)cyclopropyl)-3-methylbutanamide;-   N-(cyclopropylsulfonyl)-4-((S)-1-((R)-2-((4-fluorobenzyl)oxy)-3-methylbutanamido)ethyl)benzamide;-   (R)—N—((S)-1-(4-(1H-tetrazol-5-yl)phenyl)ethyl)-2-((3-(difluoromethoxy)benzyl)oxy)-3-methylbutanamide;-   (R)—N—((S)-1-(4-(1H-tetrazol-5-yl)phenyl)ethyl)-2-((3-cyclopropylbenzyl)oxy)-3-methylbutanamide;-   (R)-4-(1-(2-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   4-((S)-1-((R)-2-((3-cyclopropyl-4-fluorobenzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   4-(1-(3-methyl-2-((3-(oxetan-3-yl)benzyl)oxy)butanamido)cyclopropyl)benzoic    acid;-   (R)-4-(1-(2-((5-(difluoromethyl)pyridin-2-yl)methoxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   (R)-4-(1-(2-((3-cyclopropyl-4-fluorobenzyl)oxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   4-((S)-1-((R)-2-((3-(cyclopropylsulfonyl)benzyl)oxy)-3-methylbutanamido)ethyl)benzoic    acid;-   (R)-4-(1-(2-((3-(cyclopropylsulfonyl)benzyl)oxy)-3-methylbutanamido)cyclopropyl)benzoic    acid;-   4-((1S)-1-(2-cyclobutyl-2-((4-(trifluoromethyl)benzyl)oxy)acetamido)ethyl)benzoic    acid;-   4-(1-(2-cyclobutyl-2-((3-(methylsulfonyl)benzyl)oxy)acetamido)cyclopropyl)benzoic    acid;-   4-(1-(2-cyclobutyl-2-((4-(trifluoromethyl)benzyl)oxy)acetamido)cyclopropyl)benzoic    acid;-   4-(1-(2-cyclobutyl-2-((3,4-difluorobenzyl)oxy)acetamido)cyclopropyl)benzoic    acid;-   4-(1-(2-((3-chlorobenzyl)oxy)-2-cyclobutylacetamido)cyclopropyl)benzoic    acid;-   4-(1-(2-cyclobutyl-2-((3-(difluoromethoxy)benzyl)oxy)acetamido)cyclopropyl)benzoic    acid;-   (S)-4-(1-(2-cyclobutyl-2-((3-(difluoromethoxy)benzyl)oxy)acetamido)cyclopropyl)benzoic    acid;-   (R)-4-(1-(2-cyclobutyl-2-((3-(difluoromethoxy)benzyl)oxy)acetamido)cyclopropyl)benzoic    acid;

or a salt thereof.

Certain novel compounds of the invention show particularly highactivities as EP₄ receptor antagonists.

Further embodiments of the invention include the use of a compound ofFormula (1) as an EP₄ receptor antagonist. Such use may be in thetreatment of Abdominal aortic aneurysm (AAA), Ankylosing spondylitis(AS), Alzheimer's disease (AD), Atherosclerosis, Cancer includingepithelial cancers (GBD neoplasm categories of colon and rectum, lip andoral cavity, nasopharynx, other pharynx, gallbladder and biliary tract,pancreatic, non-melanoma skin, ovarian, testicular, kidney, bladder,thyroid, mesothelioma, esophageal, stomach, liver, larynx, tracheal,bronchus and lung, breast, cervical, uterine, prostate), Diabeticnephropathy, Endometriosis, Inflammatory bowel disease, Migraine,Multiple sclerosis (MS), Osteoarthritis (OA) or Rheumatoid arthritis.

Definitions

In this application, the following definitions apply, unless indicatedotherwise.

The term “treatment”, in relation to the uses of any of the compoundsdescribed herein, including those of Formula (1) is used to describe anyform of intervention where a compound is administered to a subjectsuffering from, or at risk of suffering from, or potentially at risk ofsuffering from the disease or disorder in question. Thus, the term“treatment” covers both preventative (prophylactic) treatment andtreatment where measurable or detectable symptoms of the disease ordisorder are being displayed.

The term “effective therapeutic amount” (for example in relation tomethods of treatment of a disease or condition) refers to an amount ofthe compound which is effective to produce a desired therapeutic effect.For example, if the condition is pain, then the effective therapeuticamount is an amount sufficient to provide a desired level of painrelief. The desired level of pain relief may be, for example, completeremoval of the pain or a reduction in the severity of the pain.

The terms “alkyl”, “alkoxy” “cycloalkyl”, “phenyl”, “pyridyl”“carbocyclic” and “heterocyclic” are all used in their conventionalsense (e.g. as defined in the IUPAC Gold Book), unless indicatedotherwise. “Optionally substituted” as applied to any group means thatthe said group may if desired be substituted with one or moresubstituents, which may be the same or different.

In the definitions of R⁵ and R⁶ above, where stated, one or two but notall, carbon atoms of the alkyl or cycloalkyl groups may optionally bereplaced by a heteroatom selected from O and N. Where the group is asingle carbon (C) group, the carbon cannot be replaced. It will beappreciated that when a carbon atom is replaced by a heteroatom, thelower valencies of the heteroatoms compared to carbon means that feweratoms will be bonded to the heteroatoms than would have been bonded tothe carbon atom that has been replaced. Thus, for example, replacementof a carbon atom (valency of four) in a CH₂ group by oxygen (valency oftwo) will mean that the resulting molecule will contain two lesshydrogen atoms and replacement of a carbon atom (valency of four) in aCH₂ group by nitrogen (valency of three) will mean that the resultingmolecule will contain one less hydrogen atom.

Examples of a heteroatom replacements for carbon atoms includereplacement of a carbon atom in a —CH₂—CH₂—CH₂— chain with oxygen orsulfur to give an ether —CH₂—O—CH₂— or thioether —CH₂—S—CH₂—,replacement of a carbon atom in a group CH₂—C≡C—H with nitrogen to givea nitrile (cyano) group CH₂—C≡N, replacement of a carbon atom in a group—CH₂—CH₂—CH₂— with C═O to give a ketone —CH₂—C(O)—CH₂—, replacement of acarbon atom in a group —CH₂—CH═CH₂ with C═O to give an aldehyde—CH₂—C(O)H, replacement of a carbon atom in a group —CH₂—CH₂—CH₃ with 0to give an alcohol —CH₂—CH₂—CH₂OH, replacement of a carbon atom in agroup —CH₂—CH₂—CH₃ with 0 to give an ether —CH₂—O—CH₃, replacement of acarbon atom in a group —CH₂—CH₂—CH₃ with S to give an thiol—CH₂—CH₂—CH₂SH, replacement of a carbon atom in a group —CH₂—CH₂—CH₂—with S═O or SO₂ to give a sulfoxide —CH₂—S(O)—CH₂— or sulfone—CH₂—S(O)₂—CH₂—, replacement of a carbon atom in a —CH₂—CH₂—CH₂— chainwith C(O)NH to give an amide —CH₂—CH₂—C(O)—NH—, replacement of a carbonatom in a —CH₂—CH₂—CH₂— chain with nitrogen to give an amine—CH₂—NH—CH₂—, and replacement of a carbon atom in a —CH₂—CH₂—CH₂— chainwith C(O)O to give an ester (or carboxylic acid) —CH₂—CH₂—C(O)—O—. Ineach such replacement, at least one carbon atom of the alkyl orcycloalkyl group must remain.

To the extent that any of the compounds described have chiral centres,the present invention extends to all optical isomers of such compounds,whether in the form of racemates or resolved enantiomers. The inventiondescribed herein relates to all crystal forms, solvates and hydrates ofany of the disclosed compounds however so prepared. To the extent thatany of the compounds disclosed herein have acid or basic centres such ascarboxylates or amino groups, then all salt forms of said compounds areincluded herein. In the case of pharmaceutical uses, the salt should beseen as being a pharmaceutically acceptable salt.

Salts or pharmaceutically acceptable salts that may be mentioned includeacid addition salts and base addition salts. Such salts may be formed byconventional means, for example by reaction of a free acid or a freebase form of a compound with one or more equivalents of an appropriateacid or base, optionally in a solvent, or in a medium in which the saltis insoluble, followed by removal of said solvent, or said medium, usingstandard techniques (e.g. in vacuo, by freeze-drying or by filtration).Salts may also be prepared by exchanging a counter-ion of a compound inthe form of a salt with another counter-ion, for example using asuitable ion exchange resin.

Examples of pharmaceutically acceptable salts include acid additionsalts derived from mineral acids and organic acids, and salts derivedfrom metals such as sodium, magnesium, potassium and calcium.

Examples of acid addition salts include acid addition salts formed withacetic, 2,2-dichloroacetic, adipic, alginic, aryl sulfonic acids (e.g.benzenesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic andp-toluenesulfonic), ascorbic (e.g. L-ascorbic), L-aspartic, benzoic,4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic,(+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic,citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic,ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric,gentisic, glucoheptonic, gluconic (e.g. D-gluconic), glucuronic (e.g.D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric, glycolic,hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, lactic (e.g.(+)-L-lactic and (±)-DL-lactic), lactobionic, maleic, malic (e.g.(−)-L-malic), malonic, (±)-DL-mandelic, metaphosphoric, methanesulfonic,1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic,palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic,4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic,tartaric (e.g. (+)-L-tartaric), thiocyanic, undecylenic and valericacids.

Also encompassed are any solvates of the compounds and their salts.Preferred solvates are solvates formed by the incorporation into thesolid state structure (e.g. crystal structure) of the compounds of theinvention of molecules of a non-toxic pharmaceutically acceptablesolvent (referred to below as the solvating solvent). Examples of suchsolvents include water, alcohols (such as ethanol, isopropanol andbutanol) and dimethylsulfoxide. Solvates can be prepared byrecrystallising the compounds of the invention with a solvent or mixtureof solvents containing the solvating solvent. Whether or not a solvatehas been formed in any given instance can be determined by subjectingcrystals of the compound to analysis using well known and standardtechniques such as thermogravimetric analysis (TGA), differentialscanning calorimetry (DSC) and X-ray crystallography.

The solvates can be stoichiometric or non-stoichiometric solvates.Particular solvates may be hydrates, and examples of hydrates includehemihydrates, monohydrates and dihydrates. For a more detaileddiscussion of solvates and the methods used to make and characterisethem, see Bryn et al, Solid-State Chemistry of Drugs, Second Edition,published by SSCI, Inc of West Lafayette, Ind., USA, 1999, ISBN0-967-06710-3.

The term “pharmaceutical composition” in the context of this inventionmeans a composition comprising an active agent and comprisingadditionally one or more pharmaceutically acceptable carriers. Thecomposition may further contain ingredients selected from, for example,diluents, adjuvants, excipients, vehicles, preserving agents, fillers,disintegrating agents, wetting agents, emulsifying agents, suspendingagents, sweetening agents, flavouring agents, perfuming agents,antibacterial agents, antifungal agents, lubricating agents anddispersing agents, depending on the nature of the mode of administrationand dosage forms. The compositions may take the form, for example, oftablets, dragees, powders, elixirs, syrups, liquid preparationsincluding suspensions, sprays, inhalants, tablets, lozenges, emulsions,solutions, cachets, granules, capsules and suppositories, as well asliquid preparations for injections, including liposome preparations.

The compounds of the invention may contain one or more isotopicsubstitutions, and a reference to a particular element includes withinits scope all isotopes of the element. For example, a reference tohydrogen includes within its scope ¹H, ²H (D), and ³H (T). Similarly,references to carbon and oxygen include within their scope respectively¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O. In an analogous manner, a reference toa particular functional group also includes within its scope isotopicvariations, unless the context indicates otherwise. For example, areference to an alkyl group such as an ethyl group or an alkoxy groupsuch as a methoxy group also covers variations in which one or more ofthe hydrogen atoms in the group is in the form of a deuterium or tritiumisotope, e.g. as in an ethyl group in which all five hydrogen atoms arein the deuterium isotopic form (a perdeuteroethyl group) or a methoxygroup in which all three hydrogen atoms are in the deuterium isotopicform (a trideuteromethoxy group). The isotopes may be radioactive ornon-radioactive.

Therapeutic dosages may be varied depending upon the requirements of thepatient, the severity of the condition being treated, and the compoundbeing employed. Determination of the proper dosage for a particularsituation is within the skill of the art. Generally, treatment isinitiated with the smaller dosages which are less than the optimum doseof the compound. Thereafter the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. Forconvenience, the total daily dosage may be divided and administered inportions during the day if desired.

The magnitude of an effective dose of a compound will, of course, varywith the nature of the severity of the condition to be treated and withthe particular compound and its route of administration. The selectionof appropriate dosages is within the ability of one of ordinary skill inthis art, without undue burden. In general, the daily dose range may befrom about 10 μg to about 30 mg per kg body weight of a human andnon-human animal, preferably from about 50 μg to about 30 mg per kg ofbody weight of a human and non-human animal, for example from about 50μg to about 10 mg per kg of body weight of a human and non-human animal,for example from about 100 μg to about 30 mg per kg of body weight of ahuman and non-human animal, for example from about 100 μg to about 10 mgper kg of body weight of a human and non-human animal and mostpreferably from about 100 μg to about 1 mg per kg of body weight of ahuman and non-human animal.

Pharmaceutical Formulations

While it is possible for the active compound to be administered alone,it is preferable to present it as a pharmaceutical composition (e.g.formulation).

Accordingly, in another embodiment of the invention, there is provided apharmaceutical composition comprising at least one compound of Formula(1) as defined above together with at least one pharmaceuticallyacceptable excipient.

The composition may be a tablet composition. The composition may be acapsule composition.

The pharmaceutically acceptable excipient(s) can be selected from, forexample, carriers (e.g. a solid, liquid or semi-solid carrier),adjuvants, diluents (e.g solid diluents such as fillers or bulkingagents; and liquid diluents such as solvents and co-solvents),granulating agents, binders, flow aids, coating agents,release-controlling agents (e.g. release retarding or delaying polymersor waxes), binding agents, disintegrants, buffering agents, lubricants,preservatives, anti-fungal and antibacterial agents, antioxidants,buffering agents, tonicity-adjusting agents, thickening agents,flavouring agents, sweeteners, pigments, plasticizers, taste maskingagents, stabilisers or any other excipients conventionally used inpharmaceutical compositions.

The term “pharmaceutically acceptable” as used herein means compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof a subject (e.g. a human subject) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each excipient mustalso be “acceptable” in the sense of being compatible with the otheringredients of the formulation.

Pharmaceutical compositions containing compounds of the formula (1) canbe formulated in accordance with known techniques, see for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., USA. The pharmaceutical compositions can be in any form suitablefor oral, parenteral, topical, intranasal, intrabronchial, sublingual,ophthalmic, otic, rectal, intra-vaginal, or transdermal administration.

Pharmaceutical dosage forms suitable for oral administration includetablets (coated or uncoated), capsules (hard or soft shell), caplets,pills, lozenges, syrups, solutions, powders, granules, elixirs andsuspensions, sublingual tablets, wafers or patches such as buccalpatches.

Tablet compositions can contain a unit dosage of active compoundtogether with an inert diluent or carrier such as a sugar or sugaralcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugarderived diluent such as sodium carbonate, calcium phosphate, calciumcarbonate, or a cellulose or derivative thereof such as microcrystallinecellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, and starches such as corn starch. Tablets may also containsuch standard ingredients as binding and granulating agents such aspolyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymerssuch as crosslinked carboxymethylcellulose), lubricating agents (e.g.stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT),buffering agents (for example phosphate or citrate buffers), andeffervescent agents such as citrate/bicarbonate mixtures. Suchexcipients are well known and do not need to be discussed in detailhere.

Tablets may be designed to release the drug either upon contact withstomach fluids (immediate release tablets) or to release in a controlledmanner (controlled release tablets) over a prolonged period of time orwith a specific region of the GI tract.

The pharmaceutical compositions typically comprise from approximately 1%(w/w) to approximately 95%, preferably % (w/w) active ingredient andfrom 99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient(for example as defined above) or combination of such excipients.Preferably, the compositions comprise from approximately 20% (w/w) toapproximately 90% (w/w) active ingredient and from 80% (w/w) to 10% of apharmaceutically excipient or combination of excipients. Thepharmaceutical compositions comprise from approximately 1% toapproximately 95%, preferably from approximately 20% to approximately90%, active ingredient. Pharmaceutical compositions according to theinvention may be, for example, in unit dose form, such as in the form ofampoules, vials, suppositories, pre-filled syringes, dragées, powders,tablets or capsules.

Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5%lubricants, 0-5% flow aids and/or 0-99% (w/w) fillers/or bulking agents(depending on drug dose). They may also contain 0-10% (w/w) polymerbinders, 0-5% (w/w) antioxidants, 0-5% (w/w) pigments. Slow releasetablets would in addition typically contain 0-99% (w/w)release-controlling (e.g. delaying) polymers (depending on dose). Thefilm coats of the tablet or capsule typically contain 0-10% (w/w)polymers, 0-3% (w/w) pigments, and/or 0-2% (w/w) plasticizers.

Parenteral formulations typically contain 0-20% (w/w) buffers, 0-50%(w/w) cosolvents, and/or 0-99% (w/w) Water for Injection (WFI)(depending on dose and if freeze dried). Formulations for intramusculardepots may also contain 0-99% (w/w) oils.

The pharmaceutical formulations may be presented to a patient in“patient packs” containing an entire course of treatment in a singlepackage, usually a blister pack.

The compounds of the formula (1) will generally be presented in unitdosage form and, as such, will typically contain sufficient compound toprovide a desired level of biological activity. For example, aformulation may contain from 1 nanogram to 2 grams of active ingredient,e.g. from 1 nanogram to 2 milligrams of active ingredient. Within theseranges, particular sub-ranges of compound are 0.1 milligrams to 2 gramsof active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50milligrams to 500 milligrams), or 1 microgram to 20 milligrams (forexample 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2milligrams of active ingredient).

For oral compositions, a unit dosage form may contain from 1 milligramto 2 grams, more typically 10 milligrams to 1 gram, for example 50milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound.

The active compound will be administered to a patient in need thereof(for example a human or animal patient) in an amount sufficient toachieve the desired therapeutic effect (effective amount). The preciseamounts of compound administered may be determined by a supervisingphysician in accordance with standard procedures.

EXAMPLES

The invention will now be illustrated, but not limited, by reference tothe following examples.

Examples 1 to 101

The compounds of Examples 1 to 101 shown in Table 1 below have beenprepared. In some instances compounds were obtained as a mixture ofstereoisomers, Examples 3, 6, 46, 47, 51, 92, 95, 96, 97, 98 and 99relate to such mixtures as indicated in Table 1 and Table 2. In otherinstances compounds were obtained as single isomers with or withoutassignment of stereochemistry. Examples 17, 18, 48, 49, 86, 87, 93 and94 relate to single isomers of unassigned stereochemistry as indicatedin Table 1.

TABLE 1 Example compounds

Example 1

Example 2

Example 3 (diastereomeric mixture)

Example 4

Example 5

Example 6 (diastereomeric mixture)

Example 7

Example 8

Example 9

Example 10

Example 11

Example 12

Example 13

Example 14

Example 15

Example 16

Example 17 (diastereomer 1)

Example 18 (diastereomer 2)

Example 19

Example 20

Example 21

Example 22

Example 23

Example 24

Example 25

Example 26

Example 27

Example 28

Example 29

Example 30

Example 31

Example 32

Example 33

Example 34

Example 35

Example 36

Example 37

Example 38

Example 39

Example 40

Example 41

Example 42

Example 43

Example 44

Example 45

Example 46 (diastereomeric mixture)

Example 47 (diastereomeric mixture)

Example 48 (diastereomer 1)

Example 49 (diastereomer 2)

Example 50

Example 51 (diastereomeric mixture)

Example 52

Example 53

Example 54

Example 55

Example 56

Example 57

Example 58

Example 59

Example 60

Example 61

Example 62

Example 63

Example 64

Example 65

Example 66

Example 67

Example 68

Example 69

Example 70

Example 71

Example 72

Example 73

Example 74

Example 75

Example 76

Example 77

Example 78

Example 79

Example 80

Example 81

Example 82

Example 83

Example 84

Example 85

Example 86 (enantiomer 1)

Example 87 (enantiomer 2)

Example 88

Example 89

Example 90

Example 91

Example 92 (diastereomeric mixture)

Example 93 (diastereomer 1)

Example 94 (diastereomer 2)

Example 95 (enantiomeric mixture)

Example 96 (enantiomeric mixture)

Example 97 (enantiomeric mixture)

Example 98 (enantiomeric mixture)

Example 99 (enantiomeric mixture)

Example 100

Example 101

Methods for the Preparation of Compounds of the Formula (1)

Compounds of Formula (1) can be prepared in accordance with syntheticmethods well known to the skilled person. Also provided is a process forthe preparation of a compound as defined in Formula (1) above.

Compounds of formula (1) can be prepared as outlined in Scheme 1. Amidebond formation between an acid of formula G, with an amine of formula G₂is typically conducted in the presence of a suitable coupling agent,such as HATU, and a base such as N,N-diisopropylethylamine, in solventssuch as MeCN or dichloromethane to yield the desired amide of formulaG₃. Alkylation of alcohol G₃ with an alkylating agent of formula G₄,whereby LG, represents a suitable leaving group, typically bromide.Typically, the alkylation reaction is carried out in the presence of abase, such as NaH, and in a solvent such as THF at temperatures rangingfrom 0° C. to room temperature to afford a compound of formula (1).Alternatively, a compound of formula (1) can be prepared viadisplacement of an appropriate alkylating agent G₄, whereby LG₂represents a suitable leaving group, typically mesylate, with an alcoholof formula G₅. Typical conditions comprise use of a base, such as KOtBu,and in a solvent such as THF at temperatures ranging from 0° C. to 70°C. Compounds of formula G₄ can be prepared via activation of thecorresponding alcohol of formula G₃, whereby LG₂ represents a suitableleaving group, typically mesylate. Typically, the reaction is carriedout in the presence of a base, such as triethylamine, and in a solventsuch as dichloromethane at temperatures ranging from 0° C. to roomtemperature to afford a compound of formula G₄.

In compounds where A is a protected carboxylic acid group, whereby PG,represents a suitable acid protecting group such as a methyl ester, canbe further deprotected using conditions pertinent to the nature of theprotecting group. Typically, hydrolysis of a methyl ester functionalityin the presence of a nucleophilic base such as lithium hydroxide insolvents such as MeOH or THF, affords compounds of the formula (7).

The skilled person will understand that the reaction steps depicted inScheme 1 may be combined in different ways as required to successfullyprepare the desired compound of formula (1) and formula (7). This mayinclude additional steps, for example, functional group modification,protection and/or deprotection steps into the overall syntheticsequence. For example, compounds of the formula (7) may be prepared asshown in Scheme 2.

Alkylation of an alcohol of formula G₆, whereby PG₂ represents asuitable acid protecting group such as a methyl ester, with analkylating agent of formula G₄, whereby LG represents a suitable leavinggroup, typically bromide. Typically, the alkylation reaction is carriedout in the presence of a base, such as NaH, and in a solvent such as THFat temperatures ranging from 0° C. to room temperature to afford anether of formula G₇. The resulting ester can be deprotected usingconditions pertinent to the nature of the protecting group PG₂,typically hydrolysis of a methyl ester functionality in the presence ofa nucleophilic base such as lithium hydroxide in solvents such as THF,to afford an acid of formula G₈. An amide bond forming reaction betweenan acid of formula G₈ and an amine of formula G₂, in the presence of anamide coupling reagent, such as HATU or EDCI, and a base, such astriethylamine, in a solvent such as DCM or DMF affords a compound offormula (1). In compounds where A is a protected carboxylic acid groupdeprotection can be achieved as described in Scheme 1.

It will be understood that the above schemes and procedures are notmeant to be limiting in any way. Indeed, the above schemes andprocedures can also be used to prepare compounds of the invention where,for example, A is a carboxylic acid isostere group. Methods andprotecting groups appropriate for the “A group” are well known to thoseskilled in the art, e.g. a trityl group can be used for protecting atetrazole group. Additionally, one compound of the formula 1 can beconverted into another compound of the invention by methods well knownto the skilled person. Examples of synthetic procedures for convertingone functional group into another functional group are set out instandard texts such as March's Advanced Organic Chemistry: Reactions,Mechanisms, and Structure, 7th Edition, Michael B. Smith, John Wiley,2013, (ISBN: 978-0-470-46259-1), Organic Syntheses, OnlineEdition,www.orgsyn.org, (ISSN 2333-3553) and Fiesers' Reagents for OrganicSynthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN:0-471-58283-2).

In many of the reactions described above, it may be necessary to protectone or more groups to prevent reaction from taking place at anundesirable location on the molecule. Examples of protecting groups, andmethods of protecting and deprotecting functional groups, can be foundin Greene's Protective Groups in Organic Synthesis, Fifth Edition,Editor: Peter G. M. Wuts, John Wiley, 2014, (ISBN: 9781118057483).

Compounds made by the foregoing methods may be isolated and purified byany of a variety of methods well known to those skilled in the art andexamples of such methods include recrystallisation and chromatographictechniques such as column chromatography (e.g. flash chromatography)under normal or reversed-phase conditions, HPLC and SFC.

General Procedures

Where no preparative routes are included, the relevant intermediate iscommercially available. Commercial reagents were utilized withoutfurther purification. Final compounds and intermediates are named usingChemDraw Professional, Version 17.0.0.206 (121). Room temperature (RT)refers to approximately 20-27° C. 1H NMR spectra were recorded at 400 or500 MHz on either a Bruker, Varian or Jeol instrument. Chemical shiftvalues are expressed in parts per million (ppm), i.e. (δ)—valuesrelative to the following solvents: chloroform-d=7.26 ppm, DMSO-d6=2.50ppm, methanol-d4=3.31 ppm. The following abbreviations are used for themultiplicity of the NMR signals: s=singlet, br=broad, d=doublet,t=triplet, q=quartet, m=multiplet. Coupling constants are listed as Jvalues, measured in Hz. NMR and mass spectroscopy results were correctedto account for background peaks. Chromatography refers to columnchromatography performed using 60-120 mesh or 40-633 μm, 60 Å silica geland executed under nitrogen pressure (flash chromatography) conditions.Microwave-mediated reactions were performed in Biotage Initiator or CEMDiscover microwave reactors.

LC/MS Analysis

LC/MS analysis of compounds was performed under electrospray conditionsusing the instruments and methods given below:

LC/MS Method A and LC/MS Method B

Instruments: Agilent 1260 Infinity LC with diode array detector andAgilent MS 6120; Column: Phenomenex Gemini-NX, C-18, 3 micron, 30×2 mm;Method A Gradient [time (min)/solvent B in A (%)]: 0.00/2, 0.1/2.,8.4/95, 10.0/95, 10.1/2. 12.0/2; Method B Gradient [time (min)/solvent Bin A (%)]: 0.00/5, 2.0/95, 2.5/95, 2.6/5, 3.0/5; Solvents: solventA=water (2.5 L) with 28% aqueous ammonia solution (2.5 mL); Solvent B:Acetonitrile (2.5 L) with water (125 mL) and 28% aqueous ammoniasolution (2.5 mL); column temperature: 40° C.; flow rate: 1.5 mL/min.

LC/MS Method C

Instruments: HP 1100 with G1315A DAD, Waters Micromass ZQ; Column:Phenomenex Gemini-NX C-18, 3 micron, 2.0×30 mm; Gradient [time(min)/solvent B in A (%)]: 0.00/2. 0.01/2. 8.40/95, 10.00/95; Solvents:solvent A=2.5 L H₂O+2.5 mL 28% ammonia in H₂O solution; solvent B=2.5 LMeCN+135 mL H₂O+2.5 mL 28% ammonia in H₂O solution. Injection volume 1μL; UV detection 230 to 400 nm; Mass detection 130 to 800 AMU; columntemperature 45° C.; Flow rate 1.5 mL/min.

LC/MS Method D and LC/MS Method E

Instruments: Aquity H-Class with PDA detector and QDa mass detector;Column: C-18, 1.6 micron, 50×2.1 mm; Method D Gradient [time(min)/solvent B in A (%)]: 0.00/3, 0.20/3, 2.70/98, 3.00/100, 3.50/100,3.51/3, 4.00/4; Method E Gradient [time (min)/solvent B in A (%)]:0.00/5, 0.20/5, 1.80/98, 2.00/100, 2.50/100, 2.15/5, 3.00/5; Solvents:solvent A=0.1% formic acid in water; Solvent B=0.1% formic acid inacetonitrile: water (90:10); column temperature: 35° C.; flow rate: 1mL/min.

LC/MS Method F

Instruments: Agilent Infinity II G6125C LCMS; Column: C-18, 3.5 micron,50×4.6 mm; Gradient [time (min)/solvent B in A (%)]: 0.00/8, 0.75/8,3.00/70, 3.70/95, 4.20/100, 5.20/100, 5.21/8, 7.00/8; Solvents: solventA=5 mM aqueous ammonium bicarbonate; Solvent B=methanol; columntemperature: 35° C.; flow rate: 0.9 mL/min.

LC/MS Method G

Instruments: Agilent Infinity II G6125C LCMS; Column: C-18, 3.5 micron,50×4.6 mm; Gradient [time (min)/solvent B in A (%)]: 0.00/5, 1.00/5.3.00/60, 4.50/90, 7.00/100, 8.00/100, 8.01/5, 10.0/5; Solvents: solventA=0.1% ammonia in water; Solvent B=acetonitrile; column temperature: 35°C.; flow rate: 1.0 mL/min.

LC/MS Method H

Instruments: Waters Alliance 2690 with 996 PDA detector with MicromassZQ; Column: C-18, 3.5 micron, 150×4.6 mm; Gradient [time (min)/solvent Bin A (%)]: 0.00/10, 7.00/90, 9.00/100, 14.0/100, 14.01/10, 17.00/10;Solvents: solvent A=5 mM aqueous ammonium acetate and 0.1% formic acid;Solvent B=methanol; column temperature: 35° C.; flow rate: 1.0 mL/min.

LC/MS Method I

Instruments: Waters Aquity UPLC Binary equipped with PDA and SQdetector; Column: Waters Sunfire C18, 3.5 micron, 150×4.6 mm; Isocratic[time (min)/solvent B in A (%)]: 0.00/70, 20.00/70; Solvents: solventA=5 mM aqueous Ammonium Acetate+0.1% formic acid; solvent B=methanol;column temperature: 35° C.; flow rate: 1 mL/min.

Analytical SFC Method J

Instrument: Waters Acquity UPC2 with Masslynx software, PDA detector anda QDa mass detector; Column: Phenomenex Lux Amylose-1, 3 μm, 50×2 mm;Wavelength: detection from 210 to 400 nm; Gradient [time (min)/solvent Bin A (%)]: 0.00/3, 3.00/50, 4.00/50, 5.00/3; Solvents: solvent A=C02;solvent B=IPA; column temperature: 45° C.; flow rate: 1.5 mL/min.

Analytical Chiral HPLC Method K

Instrument: Shimadzu LC 20AD; Column: CHIRALPAK IG, 5 μm, 250×4.6 mm;Isocratic [time (min)/solvent B in A (%)]: 0.00/20, 30.00/20; Solvents:solvent A=n-heptane; solvent B=2-propanol:ACN (70:30); columntemperature: RT; flow rate: 1 mL/min.

ABBREVIATIONS USED THROUGHOUT THIS DOCUMENT

-   -   aq aqueous    -   Bn benzyl    -   DCM dichloromethane    -   DMA dimethylacetamide    -   DMF dimethylformamide    -   dppf 1,1′-bis(diphenylphosphino)ferrocene    -   EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide    -   EtOAc ethyl acetate    -   HATU        1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxide hexafluorophosphate,    -   HCl hydrochloric acid    -   HOBt hydroxybenzotriazole    -   HPLC high performance liquid chromatography    -   h/hr hour    -   hrs hours    -   IPA iso-propyl alcohol    -   LC/MS liquid chromatography mass spectrometry    -   LiOH lithium hydroxide    -   M molar    -   MeCN acetonitrile    -   MeOH methanol    -   Min minutes    -   MTBE methyl tert-butyl ether    -   N normal    -   NaOH sodium hydroxide    -   NaH sodium hydride    -   prep HPLC preparative high-performance liquid chromatography    -   RM reaction mixture    -   RT room temperature    -   sat saturated    -   THF tetrahydrofuran    -   UPLC ultra performance liquid chromatography    -   V volumes

GENERAL SYNTHETIC PROCEDURES FOR THE EXAMPLES Route A Procedure for thePreparation of Example 1,4-((S)-1-((R)-3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)ethyl)benzoicacid

Step (i): To an ice cooled solution of Intermediate 1, methyl4-((S)-1-((R)-2-hydroxy-3-methylbutanamido)ethyl) benzoate (11.3 g, 40.6mmol) and potassium tert-butoxide (5.01 g, 44.7 mmol) in DMF (100 mL)was added 4-(trifluoromethyl)benzyl bromide (10.7 g, 44.7 mmol). Themixture was warmed to RT and stirred for 6 hrs, after which it waspartitioned between EtOAc and water. The organics were separated, washedwith brine (×2) dried over MgSO₄ and concentrated. The crude materialwas purified by flash column chromatography (normal phase, silica) undera gradient of EtOAc (0% to 50%) in iso-hexane to afford methyl4-[(1S)-1-[[(2R)-3-methyl-2-[[4-(trifluoromethyl)phenyl]methoxy]butanoyl]amino]ethyl]benzoate(8.93 g, 20.4 mmol, 50% yield) as a white solid. (LC/MS Method B): m/z438 [M+H]⁺ (ES⁺), at 1.75 min, UV active.

Step (ii): To a solution of methyl4-[(1S)-1-[[(2R)-3-methyl-2-[[4-(trifluoromethyl)phenyl]methoxy]butanoyl]amino]ethyl]benzoate(7.44 g, 17.0 mmol) in water (28 mL) and methanol (15 mL) was addedsodium hydroxide (3.40 g, 85.0 mmol) and the reaction mixture heated to70° C. for 5 hrs. The mixture was cooled to RT and partitioned betweenethyl acetate and 1 M HCl. The organics were separated, dried viapassage through a hydrophobic frit and concentrated. The crude materialwas triturated from diethyl ether and then recrystallised from a minimalamount of boiling isopropanol to afford Example 1,4-((S)-1-((R)-3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)ethyl)benzoicacid (3.12 g, 7.4 mmol, 43.3% yield) as a white solid. Data available inTable 2.

Route B Procedure for the Preparation of Example 2,(R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)cyclopropyl)benzoicacid

Step (i): To an ice cooled mixture of Intermediate 5 methyl(R)-4-(1-(2-hydroxy-3-methylbutanamido)cyclopropyl)benzoate (212 mg,0.73 mmol) in THF (3.6 ml) was added NaH (60% dispersion in mineral oil)(32 mg, 0.8 mmol) and the reaction mixture stirred for 10 minutes atroom temperature after which Intermediate 311-(bromomethyl)-4-(trifluoromethyl)benzene (192 mg, 0.8 mmol) was added.The reaction was stirred at RT for 18 hours then partitioned betweenwater and EtOAc, the organics separated, washed with brine, dried(hydrophobic frit.) and concentrated. The crude material was purified byflash column chromatography (normal phase) [gradient 0-45% EtOAc iniso-hexane] to give methyl(R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)cyclopropyl)benzoate as an orange solid (76 mg, 0.17 mmol, 23% yield). LC/MS (MethodC): m/z 450 [M+H]⁺, 1.73 min.

Step (ii): Methyl(R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)cyclopropyl) benzoate (76 mg, 0.17 mmol), was suspended in 1,4-dioxane(0.4 mL) and water (0.4 mL) and lithium hydroxide monohydrate (28 mg,0.68 mmol) added. The reaction mixture stirred at room temperature for18 hours then concentrated in vacuo The crude material was purified byflash column chromatography (reverse phase) [gradient 10-45% MeOH inwater and 0.2% 28% NH₄OH (aq.) solution)]. To give Example 2(R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)cyclopropyl) benzoic acid (36 mg, 0.08 mmol, 49%), as a white solid.Data available in Table 2 Alternate route to Example 2

Step (i): In a flask was taken methyl R-2-hydroxy-3-methyl-butanoate (25g, 1.0 eq.) in dry THF (10 V) at 0° C. Then tetrabutylammonium iodide(0.1 eq.) and Intermediate 31 1-(bromomethyl)-4-(trifluoromethyl)benzene(44 g, 1.0 eq.) were added the RM was stirred for 15 min then NaH (1.5eq.) was added portion wise with temperature maintained at 0° C.throughout. The reaction mixture was stirred at 0° C. for 1 hour thenthe RM was stirred at room temperature for 4 hrs. After completion ofthe reaction, the reaction mixture was quenched with ice-cold water (10V), and product was extracted with MTBE (3V x 3), the extracts werecombined and evaporated under vacuum to afford 40 g of the crudeproduct. The crude compound was purified by column chromatography using60-120 mesh silica gel and the product was eluted in 1-2% ethyl acetateand hexane system to afford methyl(R)-3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanoate 25 g as aviscus liquid.

Step (ii): Methyl(R)-3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanoate (75 g, 1.0 eq.)in THF (3 V) was treated with LiOH (1.5 eq.) and water (1.5 V) at RT andthen stirred at 80° C. for 4 hrs. After completion of the reaction, THFwas evaporated under vacuum and obtained residue was taken in water (5V) and washed with MTBE (5 V). Then aq. layer was acidified with 1N aq.HCl (pH ˜2). Product was then extracted with DCM (20 V×2). The combinedorganic layer was evaporated under vacuum to obtain(R)-3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanoic acid (62 g).This compound was used in the next step without any furtherpurification.

Step (iii): In a flask was taken(R)-3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanoic acid (62 g, 1.0eq.) in DMF (10 V) at 0° C. followed by the addition of HATU (1.5 eq.),methyl 4-(1-aminocyclopropyl)benzoate (1.0 eq.) and DIPEA (3.0 eq.) atsame temperature. Then the reaction mixture was allowed warm to RT withcontinued stirring. After completion of the reaction, the reactionmixture was poured in water (10 V) The obtained solid was filtered,washed with cooled Water (2 V) and dried under vacuum to give 105 g ofthe crude product. The crude compound was purified by columnchromatography using 60-120 mesh silica gel and the product was elutedin 10-15% ethyl acetate and hexane system to afford methyl(R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)cyclopropyl)benzoate as a viscus liquid 58 g

Step (iv): In a flask was taken methyl(R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)cyclopropyl)benzoate (58 g, 1.0 eq.) in THF (3 V) and water (1.5 V). The reactionmixture was cooled to 0-5° C. followed by the addition of Lithiumhydroxide monohydrate (3.0 eq.) Portion wise over a period of 30 min. atsame temperature. Then the reaction mixture was heated to 80° C. over aperiod of 30 min and further stirred for 4 hrs at 80° C. Aftercompletion of the reaction, solvent was evaporated under vacuum. Thenwater (5 V) was added into the reaction mixture. This aq. layer waswashed with MTBE (5 V). Then aq. layer was acidified with 1 N aq. HCl(pH: 2 to 3) and product was extracted in ethyl acetate (20 V x 3). Thecombined organic layer was washed with water and evaporated under vacuumto give Example 2(R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)cyclopropyl)benzoicacid (43 g) as an off-white solid.

Additional Purification—This material and material from additionalbatches (79 g) were further purified by being taken up in heptane (10 V)and heated to 80° C., followed by the addition of IPA (3 V) at sametemperature. Then the mixture was allowed to cool to room temperatureand stirred for 30 min. The obtained solid was filtered, washed withn-heptane (3 V) and dried under vacuum (this was repeated twice).Combined product materials (85 g) were suspended in n-heptane (425 mL, 5V) at room temperature and stirred for 30 min. The solid was filtered,washed with n-heptane (2 V) and dried under vacuum to give of Example 2(R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)cyclopropyl) benzoic acid (82 g). Data available in Table 2.

Route C Procedure for the Preparation of Example 5,4-((S)-1-((R)-2-((4-fluorobenzyl)oxy)-3-methylbutanamido)ethyl)benzoicacid

Step (i): To a suspension of NaH (60% in mineral oil) (0.071 g, 1.77mmol) in DMF (5 mL) under an atmosphere of nitrogen at 0° C. was addedIntermediate 1, methyl 4-((S)-1-((R)-2-hydroxy-3-methylbutanamido)ethyl)benzoate (0.45 g, 1.61 mmol). The mixture was stirred at the sametemperature for 10 mins, after which 1-(bromomethyl)-4-fluorobenzene(0.36 g, 1.93 mmol) was added. The mixture was warmed to RT and stirredfor 3 hr after which it was partitioned between EtOAc and water. Theorganics were separated, and the aqueous layer was further extractedwith EtOAc (×2). The combined organics were dried over Na₂SO₄ andconcentrated. The residue was purified by flash column chromatography(reversed phase, C18) under a gradient of MeCN (0-62%) in water toafford methyl4-((S)-1-((R)-2-((4-fluorobenzyl)oxy)-3-methylbutanamido)ethyl) benzoate(0.38 g, 0.99 mmol, 61% yield) as a white solid. (LC/MS Method D): m/z388 [M+H]⁺ (ES⁺), at 2.67 min, UV active.

Step (ii): To a solution of methyl4-((S)-1-((R)-2-((4-fluorobenzyl)oxy)-3-methylbutanamido)ethyl) benzoate(0.38 g, 0.98 mmol) in 1,4-dioxane (4 mL) and water (2 mL) was addedlithium hydroxide monohydrate (0.21 g, 4.90 mmol). The mixture wasstirred at RT for 5 hrs, after which it was acidified to pH 4 withglacial acetic acid and concentrated under reduced pressure. The residuewas purified by flash column chromatography (reversed phase, C18) undera gradient of MeCN (0-50%) in water to afford Example 5,4-((S)-1-((R)-2-((4-fluorobenzyl)oxy)-3-methylbutanamido)ethyl) benzoicacid (0.28 g, 0.75 mmol, 76%) as an off white solid. Data available inTable 2.

Route D Procedure for the Preparation of Example 6,4-((1S)-1-(2-((4-methoxybenzyl)oxy)-3-methylbutanamido)ethyl)benzoicacid, Mixture of Diastereomers

To a solution of (4-methoxyphenyl)methanol (0.20 g, 1.47 mmol) in THF(3.5 mL) at 0° C. was added potassium tert-butoxide and the mixture wasstirred at the same temperature for 20 mins. Intermediate 3, methyl4-((1S)-1-(3-methyl-2-((methylsulfonyl)oxy)butanamido) ethyl)benzoate(0.35 g, 0.98 mmol) was added and the mixture was stirred at 80° C. for4 hrs, after which it was cooled to RT and partitioned between EtOAc andwater. The aqueous layer was separated, acidified to pH 1 with 1 N HCland extracted with EtOAc (×2). The combined organics were dried overNa₂SO₄ and concentrated. Note partial ester hydrolysis occurred in thereaction. The residue was purified by flash column chromatography(reversed phase, C18) under a gradient of MeCN (0-36%) in water toafford Example 6, 4-((1S)-1-(2-((4-methoxybenzyl)oxy)-3-methylbutanamido)ethyl)benzoic acid(0.13 g, 0.33 mmol, 34% yield) as a white solid. Data available in Table2.

Route E Procedure for the Preparation of Example 11,4-((S)-1-((R)-2-((4-chlorobenzyl)oxy)-3-methylbutanamido)ethyl)benzoicacid

Step (i): To a suspension of NaH (˜60% in mineral oil) (0.05 g, 1.34mmol) in DMF (2 mL) under an atmosphere of nitrogen at 0° C. was addedIntermediate 1, methyl 4-((S)-1-((R)-2-hydroxy-3-methylbutanamido)ethyl)benzoate (0.25 g, 0.89 mmol). The mixture was stirred at the sametemperature for 15 mins, after which 1-(bromomethyl)-4-chlorobenzene(0.27 g, 1.34 mmol) was added. The mixture was warmed to RT and stirredfor 1 hr after which it was partitioned between EtOAc and water. Theorganics were separated, and the aqueous layer was further extractedwith EtOAc (×2). The combined organics were dried over Na₂SO₄ andconcentrated. The residue was purified by flash column chromatography(reversed phase, C18) under a gradient of MeCN (0-90%) in water toafford methyl4-((S)-1-((R)-2-((4-chlorobenzyl)oxy)-3-methylbutanamido)ethyl)benzoate(0.143 g, 0.35 mmol, 40% yield) as a sticky liquid. (LC/MS Method E):m/z 404 [M+H]⁺ (ES⁺), at 1.91 min, UV active.

Step (ii): To a solution of methyl4-((S)-1-((R)-2-((4-chlorobenzyl)oxy)-3-methylbutanamido)ethyl) benzoate(0.14 g, 0.35 mmol) in 1,4-dioxane (2 mL) and water (1 mL) was addedlithium hydroxide monohydrate (70 mg, 1.77 mmol). The mixture wasstirred at RT for 3 hrs, after which it was acidified to pH 4 withglacial acetic acid and concentrated under reduced pressure. The residuewas purified by flash column chromatography (reversed phase, C18) undera gradient of MeCN (0-56%) in water to afford Example 11,4-((S)-1-((R)-2-((4-chlorobenzyl)oxy)-3-methylbutanamido)ethyl)benzoicacid (100 mg, 0.26 mmol, 74% yield) as a brown solid. Data available inTable 2.

Route F Procedure for the Preparation of Example 13,4-((S)-1-((R)-2-((4-(difluoromethyl)benzyl)oxy)-3-methylbutanamido)ethyl)benzoicacid

Step (i): To a suspension of NaH (˜60% in mineral oil) (0.08 g, 2.15mmol) in DMF (5 mL) under an atmosphere of nitrogen at 0° C. was addedIntermediate 1, methyl 4-((S)-1-((R)-2-hydroxy-3-methylbutanamido)ethyl)benzoate (0.20 g, 0.71 mmol). The mixture was stirred at the sametemperature for 15 mins, after which 1-(bromomethyl)-4-(difluoromethyl)benzene (0.23 g, 1.07 mmol) was added. The mixture was stirred at 0° C.for 2 hrs after which it was acidified to pH 1 by the addition of 1 NHCl and then partitioned between EtOAc and water. The organics wereseparated, and the aqueous layer was further extracted with EtOAc (×2).The combined organics were dried over Na₂SO₄ and concentrated, and theresidue was purified by flash column chromatography (reversed phase,C18) under a gradient of MeCN (0-72%) in water to afford Example 11,4-((S)-1-((R)-2-((4-(difluoromethyl)benzyl)oxy)-3-methylbutanamido)ethyl)benzoicacid (82 mg, 0.20 mmol, 29% yield) as a white solid. Data available inTable 2.

Route G Procedure for the Preparation of Example 17,4-((1S)-1-(2-((3-fluorobenzyl)oxy)-3-methylbutanamido)ethyl)benzoicacid, Diastereomer 1 and Example 18,4-((1S)-1-(2-((3-fluorobenzyl)oxy)-3-methylbutanamido)ethyl)benzoicacid, Diastereomer 2

Step (i):4-((1S)-1-(2-((3-fluorobenzyl)oxy)-3-methylbutanamido)ethyl)benzoic acid(110 mg, synthesized according to Route E) was separated into singlediastereomers via chiral preparative HPLC [Chiralpak IG, 21×250 mm, 5μm, 23 mL per min; Gradient [time (min)/solvent B in A (%)]: 0.01/8,40.00/8; Solvents: solvent A=0.1% TFA and 0.1% diethylamine in hexane;solvent B=methanol:IPA (60:40)] to afford4-((1S)-1-(2-((3-fluorobenzyl)oxy)-3-methylbutanamido)ethyl)benzoicacid, diastereomer 1 (29 mg, 0.078 mmol) as a white solid, and4-((1S)-1-(2-((3-fluorobenzyl)oxy)-3-methylbutanamido)ethyl)benzoicacid, diastereomer 2 (29 mg, 0.078 mmol) as a white solid. Dataavailable in Table 2.

Route H Procedure for the Preparation of Example 42,(R)—N—((S)-1-(4-(1H-tetrazol-5-yl)phenyl)ethyl)-2-((4-fluorobenzyl)oxy)-3-methylbutanamide

Step (i): To a suspension of NaH (˜60% in mineral oil) (45 mg, 1.11mmol) in DMF (3 mL) under an atmosphere of nitrogen at 0° C. was addedIntermediate 4,(R)—N—((S)-1-(4-cyanophenyl)ethyl)-2-hydroxy-3-methylbutanamide (0.25 g,1.01 mmol). The mixture was stirred at the same temperature for 15 mins,after which 1-(bromomethyl)-4-fluorobenzene (0.29 g, 1.52 mmol) wasadded and the mixture was stirred at RT for 2 hrs. The mixture waspartitioned between EtOAc and water and the organics were separated. Theaqueous layer was further extracted with EtOAc (×2) and the combinedorganics were dried over Na₂SO₄ then concentrated. The residue waspurified by flash column chromatography (reversed phase, C18) under agradient of MeCN (0-74%) in water to afford (R)—N—((S)-1-(4-cyanophenyl)ethyl)-2-((4-fluorobenzyl)oxy)-3-methylbutanamide (0.20 g, 0.56 mmol,56% yield) as a yellow solid. (LC/MS Method E): m/z 355 [M+H]⁺ (ES⁺), at1.73 min, UV active.

Step (ii): A mixture of(R)—N—((S)-1-(4-cyanophenyl)ethyl)-2-((4-fluorobenzyl)oxy)-3-methylbutanamide (0.10 g, 0.28 mmol), NaN₃ (0.11 g, 1.69 mmol)and NH₄Cl (90 mg, 1.69 mmol) in DMF (1 mL) was heated to 80° C. for 7hrs. The mixture was cooled to RT then partitioned between EtOAc andwater. The organics were separated, and the aqueous layer was furtherextracted with EtOAc (×2). The combined organics were dried over Na₂SO₄,concentrated, and the crude material was purified by flash columnchromatography (reversed phase, C18) under a gradient of MeCN (0-45%) inwater to afford Example 42,(R)—N—((S)-1-(4-(1H-tetrazol-5-yl)phenyl)ethyl)-2-((4-fluorobenzyl)oxy)-3-methylbutanamide(0.064 g, 57.06%) as a yellow solid. Data available in Table 2.

Route I Procedure for the Preparation of Example 45,4-((S)-1-((R)-2-((3-(hydroxymethyl)benzyl)oxy)-3-methylbutanamido)ethyl)benzoicacid

Step (i): To a suspension of NaH (˜60% in mineral oil) (24 mg, 0.60mmol) in DMF (2 mL) under an atmosphere of nitrogen at 0° C. was addedIntermediate 1, methyl 4-((S)-1-((R)-2-hydroxy-3-methylbutanamido)ethyl)benzoate (0.15 g, 0.54 mmol). The mixture was stirred at the sametemperature for 10 mins, after which 3-(bromomethyl)benzaldehyde (0.16g, 0.81 mmol) was added. The mixture was warmed to RT and stirred for 2hr after which it was partitioned between EtOAc and water. The organicswere separated, and the aqueous layer was further extracted with EtOAc(×2). The combined organics were dried over Na₂SO₄ and concentrated. Theresidue was purified by flash column chromatography (reversed phase,C18) under a gradient of MeCN (0-74%) in water to afford methyl4-((S)-1-((R)-2-((3-formylbenzyl)oxy)-3-methylbutanamido)ethyl)benzoate(0.14 g, 0.35 mmol, 66% yield) as an off-white solid. (LC/MS Method D):m/z 398 [M+H]⁺ (ES⁺), at 2.46 min, UV active.

Step (ii): To a solution of methyl4-((S)-1-((R)-2-((3-formylbenzyl)oxy)-3-methylbutanamido)ethyl)benzoate(0.13 g, 0.33 mmol) in 1,4-dioxane (1 mL) and water (0.5 mL) was addedlithium hydroxide monohydrate (70 mg, 1.64 mmol). The mixture wasstirred at RT for 2 hrs, after which it was acidified to pH 1 with 1 NHCl and partitioned between EtOAc and water. The organics wereseparated, the acidic aqueous layer was further extracted with EtOAc(×2) and the combined organics were concentrated to afford4-((S)-1-((R)-2-((3-formylbenzyl)oxy)-3-methylbutanamido)ethyl)benzoicacid (0.13 g, 0.33 mmol, 100% yield) as an off-white solid. (LC/MSMethod D): m/z 384 [M+H]⁺ (ES⁺), at 2.15 min, UV active.

Step (iii): To a solution of4-((S)-1-((R)-2-((3-formylbenzyl)oxy)-3-methylbutanamido) ethyl)benzoicacid (0.12 g, 0.31 mmol) in MeOH (3 mL) at 0° C. was added NaBH₄ (0.12g, 0.31 mmol). The mixture was stirred at RT for 1 hr, after which itwas acidified to pH 1 with 1 N HCl and partitioned between EtOAc andwater. The organics were separated, and the acidic aqueous layer wasfurther extracted with EtOAc. The combined organics were concentratedand the residue was purified by flash column chromatography (reversedphase, C18) under a gradient of MeCN (0-35%) in water to afford Example45,4-((S)-1-((R)-2-((3-(hydroxymethyl)benzyl)oxy)-3-methylbutanamido)ethyl)benzoicacid (60 mg, 0.16 mmol, 50% yield) as a white solid. Data available inTable 2.

Route J Procedure for the Preparation of Example 47,4-((1S)-1-(3-methyl-2-((4-(oxetan-3-yl)benzyl)oxy)butanamido)ethyl)benzoicacid

Step (i): Intermediate 35, (4-(oxetan-3-yl)phenyl)methanol (0.30 g, 1.82mmol) was added to a stirred suspension of NaH (˜60% in mineral oil)(0.08 g, 2.01 mmol) in DMF (3 mL) at 0° C. under nitrogen atmosphere andreaction mixture was stirred at room temperature for 15 min.Intermediate 3, methyl4-((1S)-1-(3-methyl-2-((methylsulfonyl)oxy)butanamido)ethyl)benzoate(0.91 g, 2.56 mmol) was then added and the reaction mixture was allowedto stir at room temperature for 2 hrs. The reaction mixture was quenchedwith saturated aqueous NH₄Cl solution (3 mL) and the reaction mixturewas partitioned between water (70 mL) and EtOAc (60 mL). The aqueouslayer was further extracted with EtOAc (2×25 mL). Organic layers werecombined and dried (Na₂SO₄). Solvent was removed in vacuo and the crudeproduct was purified by reverse phase gradient flash columnchromatography (reverse phase, C18 silica), product eluted at 0% to 57%ACN in water to afford crude methyl4-((1S)-1-(3-methyl-2-((4-(oxetan-3-yl)benzyl)oxy)butanamido)ethyl)benzoate (011 g, 15%) as a yellow sticky solid. (LC/MS Method D):m/z 426 [M+H]⁺ (ES⁺), at 2.17 and 2.21 min, UV active.

Step (ii): To a solution of methyl4-((1S)-1-(3-methyl-2-((4-(oxetan-3-yl)benzyl)oxy)butanamido)ethyl)benzoate (0.11 g, 0.27 mmol) in Dioxane (1.0 mL) and water (1.0mL) was added LiOH monohydrate (0.034 g, 0.81 mmol) at room temperatureand the reaction mixture was allowed to stir at room temperature for 3hrs. The reaction mixture was then acidified with glacial acetic acid(0.3 mL) to adjust to pH ˜4 and concentrated in vacuo. The obtainedcrude product was purified by reverse phase gradient flash columnchromatography (reverse phase, C18 silica), product was eluted at 0% to35% ACN in water to afford pure Example 47,4-((1S)-1-(3-methyl-2-((4-(oxetan-3-yl)benzyl)oxy)butanamido)ethyl)benzoicacid (0.042 g, 39%) as a white solid. Data available in Table 2.

Route K Procedure for the Preparation of Example 48,4-((1S)-1-(3-methyl-2-((3-(oxetan-3-yl)benzyl)oxy)butanamido)ethyl)benzoicacid, diastereomer 1, and Example 49,4-((1S)-1-(3-methyl-2-((3-(oxetan-3-yl)benzyl)oxy)butanamido)ethyl)benzoicacid, Diastereomer 2

Step (i): A solution of Intermediate 36, (3-(oxetan-3-yl)phenyl)methanol (0.10 g, 0.60 mmol) in THF (1 mL) was added to a stirredsuspension of potassium tert-butoxide (0.20 g, 1.82 mmol) in THF (2 mL)at room temperature, under a nitrogen atmosphere, and the reactionmixture was stirred for 15 min. Intermediate 3, methyl4-((1S)-1-(3-methyl-2-((methylsulfonyl)oxy)butanamido)ethyl)benzoate(0.32 g, 0.91 mol) was added and the reaction mixture was allowed tostir at room temperature for 3 hrs. The reaction mixture was partitionedbetween water (30 mL) and EtOAc (50 mL). The aqueous layer was furtherextracted with EtOAc (2×30 mL). The organic layers were combined anddried (Na₂SO₄), the solvent was removed in vacuo and the crude productwas purified by reverse phase gradient flash column chromatography(reverse phase, C18 silica), product eluted at 0% to 67% ACN in water toafford pure methyl 4-((1S)-1-(3-methyl-2-((3-(oxetan-3-yl)benzyl)oxy)butanamido)ethyl)benzoate (0.060 g, 16%) as colorless sticky solid.(LC/MS Method D): m/z 426 [M+H]⁺ (ES⁺), at 2.15 min, UV active.

Step (ii): LiOH monohydrate (0.030 g, 0.70 mmol) was added to a solutionof methyl 4-((1S)-1-(3-methyl-2-((3-(oxetan-3-yl)benzyl)oxy)butanamido)ethyl) benzoate (0.060 g, 0.14 mmol) in dioxane (1.0 mL)and water (0.5 mL) at room temperature and the reaction mixture wasallowed to stir at room temperature for 3 hrs. The reaction mixture wasthen acidified with glacial acetic acid (0.3 mL) to adjust to pH ˜4 andconcentrated in vacuo. The obtained crude product was purified byreverse phase gradient flash column chromatography (reverse phase, C18silica), product was eluted at 0% to 56% ACN in water to afford pure4-((1S)-1-(3-methyl-2-((3-(oxetan-3-yl)benzyl)oxy)butanamido)ethyl)benzoicacid (0.045 g, 78%) as a colourless, sticky solid. (LC/MS Method D): m/z412 [M+H]⁺ (ES⁺), at 1.87 & 1.89 min, UV active.

Diastereomer Separation:4-((1S)-1-(3-Methyl-2-((3-(oxetan-3-yl)benzyl)oxy)butanamido)ethyl)benzoicacid was separated into single diastereomers via chiral preparative HPLC[Chiralpak IG SFC, 21×250 mm, 5 μm, 16 mL per min; Gradient [time(min)/solvent B in A (%)]: 0.01/20, 45.00/20; Solvents: solventA=n-heptane; solvent B=methanol:IPA (30:70)] to afford Example 47,4-((1S)-1-(3-methyl-2-((3-(oxetan-3-yl)benzyl)oxy)butanamido)ethyl)benzoicacid; diastereomer 1, (0.010 g, 22%) as an off-white solid, and Example48, 4-((1S)-1-(3-methyl-2-((3-(oxetan-3-yl)benzyl)oxy)butanamido)ethyl)benzoic acid; diastereomer 2, (0.0091 g, 20%) as awhite solid. Data available in Table 2.

Route L Procedure for the Preparation of Example 38,4-((S)-1-((R)-2-((3-hydroxybenzyl)oxy)-3-methylbutanamido)ethyl)benzoicacid

Step (i): K₂CO₃ (0.08 g, 0.58 mmol) and Pd(PPh₃)₄ (0.017 g, 0.014 mmol)was added to a solution of4-((S)-1-((R)-2-((3-(allyloxy)benzyl)oxy)-3-methylbutanamido)ethyl)-benzoicacid (0.12 g, 0.29 mmol) in dichloromethane (2 mL) and methanol (2 mL)at room temperature. The reaction was then heated to 50° C. for 4 hrs.The reaction mixture was concentrated in vacuo to obtain crude productwhich was purified by two times reverse phase gradient flash columnchromatography (reverse phase, C18 silica), product was eluted at 0% to56% ACN in 0.1% FA in water to afford pure Example 38,4-((S)-1-((R)-2-((3-hydroxybenzyl)oxy)-3-methylbutanamido)ethyl)-benzoicacid (0.045 g, 40%) as an off white solid. Data available in Table 2.

Route M Procedure for the Preparation of Example 51,4-((1S)-1-((2R)-3-methyl-2-(1-(4-(trifluoromethyl)phenyl)ethoxy)butanamido)ethyl)benzoicacid

Step (i): Intermediate 1, methyl4-((S)-1-((R)-2-hydroxy-3-methylbutanamido) ethyl)benzoate (0.20 g, 0.71mmol) was added to a stirred suspension of NaH (˜60% in mineral oil)(0.034 g, 0.85 mmol) in DMF (4 mL) at 0° C. under nitrogen atmosphereand the reaction mixture was stirred at 0° C. for 10 min. After thistime, Intermediate 39, 1-(1-bromoethyl)-4-(trifluoromethyl)benzene (0.27g, 1.07 mmol) was added and the reaction mixture was stirred at roomtemperature for 4 hrs. The reaction mixture was then partitioned betweensaturated aqueous NH₄Cl solution (40 mL) and EtOAc (30 mL). The aqueouslayer was further extracted with EtOAc (2×50 mL). The organic layerswere combined and dried (Na₂SO₄), the solvent removed in vacuo and thecrude product was purified by reverse phase gradient flash columnchromatography (reverse phase, C18 silica), product eluted at 0% to 46%ACN in water to afford crude product which was further purified byPrep-TLC using 70% EtOAc: Hexane to yield pure Example 51,4-((1S)-1-((2R)-3-methyl-2-(1-(4-(trifluoromethyl)phenyl)ethoxy)butanamido)ethyl)benzoic acid: (0.020 g, 6.4%) as a brown sticky solid.Data available in Table 2.

Route N Procedure for the Preparation of Example 53,4-((S)-1-((R)-3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)ethyl)-N-(methylsulfonyl)benzamide

Step (i): To a solution of Example 1,4-[(1S)-1-[[(2R)-3-methyl-2-[[4-(trifluoromethyl)phenyl]methoxy]butanoyl]amino]ethyl]benzoicacid (150 .mg, 0.350 mmol), DMAP (129.84 mg, 1.06 mmol) and EDCI (101.86mg, 0.530 mmol) in DCM (1.5 mL) was added methanesulfonamide (84.24 mg,0.890 mmol). The mixture was stirred at RT for 3 days after which it wasdiluted with DCM. the mixture was washed with water and brine, dried(frit) and concentrated. The crude material was purified by reversephase HPLC (Gilson Semi Preparative HPLC System, Gemini-NX, 5μ, C18,100×30 mm) eluted at 5-85% ACN in Water with 0.2% of 28% Ammoniasolution to afford Example 53,N-methylsulfonyl-4-[(1S)-1-[[(2R)-3-methyl-2-[[4-(trifluoromethyl)phenyl]methoxy]butanoyl]amino]ethyl]benzamide(99 mg, 56% yield) as a colourless oil. Data available in Table 2.

Route O Procedure for the Preparation of Example 73,(R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)cyclobutyl)benzoicacid

Step (i): To an ice cooled solution of Intermediate 43,(2R)—N-[1-(4-cyanophenyl)cyclobutyl]-2-hydroxy-3-methyl-butanamide (109mg, 0.400 mmol) and potassium tert-butoxide (49.4 mg, 0.440 mmol) wasadded Intermediate 31, 4-(trifluoromethyl)benzyl bromide (105 mg, 0.440mmol) and the reaction mixture stirred for 4 hours at RT. The reactionmixture was partitioned between ethyl acetate and water after which theorganics were separated, washed with brine, dried (frit.) andconcentrated. The residue was purified by flash column chromatography(normal phase, [5.9×2.0 cm (10 g)], Biotage® SNAP KP-Sil—50 μm irregularsilica, 30 mL per min, [gradient 0% to 50% Ethyl Acetate in Iso-hexane],to afford(R)—N-(1-(4-cyanophenyl)cyclobutyl)-3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamide(109 mg, 63% yield) as a colourless oil. (LC/MS Method B): m/z 431[M+H]⁺ (ES⁺), at 1.76 min, UV active.

Step (ii): A suspension of(R)—N-(1-(4-cyanophenyl)cyclobutyl)-3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamide(109 .mg, 0.250 mmol) in 5M (aq) sodium hydroxide (0.8 mL, 4 mmol) andEthanol (0.42 mL) was heated to reflux for 18 hours after which it wasconcentrated. The crude material was partitioned between ethyl acetateand 1 M HCl, dried (frit.) and concentrated. The crude material waspurified by reverse phase HPLC under basic conditions (Gilson SemiPreparative HPLC System, Gemini-NX, 5μ, C18, 100×30 mm) eluted at 50-80%ACN in Water with 0.2% of 28% Ammonia solution to afford Example 73,(R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)cyclobutyl)benzoicacid (3 mg, 2.6% yield) which was scratched to give a white solid. Dataavailable in Table 2.

Route P Procedure for the Preparation of Example 92,4-((1S)-1-(2-cyclobutyl-2-((4-(trifluoromethyl)benzyl)oxy)acetamido)ethyl)benzoicacid, Example 93,4-((1S)-1-(2-cyclobutyl-2-((4-(trifluoromethyl)benzyl)oxy)acetamido)ethyl)benzoicacid, Diastereomer 1, and Example 94,4-((1S)-1-(2-cyclobutyl-2-((4-(trifluoromethyl)benzyl)oxy)acetamido)ethyl)benzoicacid, Diastereomer 2

Step (i): To an ice cooled solution of methyl2-cyclobutyl-2-hydroxy-acetate (100 mg, 0.69 mmol) and potassiumtert-butoxide (85 mg, 0.76 mmol) in DMF (3.5 mL) was added4-(trifluoromethyl)benzyl bromide (182 mg, 0.76 mmol) and the reactionmixture warmed to RT and stirred for 18 hrs. The reaction mixture waspartitioned between EtOAc and water after which the organics wereseparated, washed with brine, dried via passage through a hydrophobicfrit and concentrated. The crude material was purified by flash columnchromatography (normal phase) [gradient 0-40% EtOAc in Iso-hexane] toafford methyl 2-cyclobutyl-2-((4-(trifluoromethyl)benzyl)oxy)acetate (79mg, 0.26 mmol, 38%) as a colourless oil. LC/MS (Method B): m/z 303[M+H]⁺ (ES⁺), at 1.79 min, UV active.

Step (ii): To a suspension of methyl2-cyclobutyl-2-((4-(trifluoromethyl)benzyl)oxy)acetate (79 mg, 0.26mmol) in 1,4-dioxane (0.6 mL) and water (0.6 mL) was added lithiumhydroxide monohydrate (44 mg, 1.06 mmol). The reaction mixture wasstirred at RT for 18 hrs then concentrated. The crude material waspartitioned between 1 M HCl (aq.) and EtOAc and the organics separated.The aqueous layer was further extracted with EtOAc and the combinedorganics were dried via passage through a hydrophobic frit andconcentrated to afford2-cyclobutyl-2-((4-(trifluoromethyl)benzyl)oxy)acetic acid (76 mg, 0.26mmol, quantitative) as a colourless oil. The crude material was usedwithout any further purification. LC/MS (Method B): m/z 311 [M+Na]⁺(ES⁺), at 0.68 min, UV active.

Step (iii): Methyl 4-[(1S)-1-aminoethyl]benzoate (51 mg, 0.29 mmol),2-cyclobutyl-2-((4-(trifluoromethyl)benzyl)oxy)acetic acid (76 mg, 0.26mmol), EDC (76 mg, 0.40 mmol) and HOBt monohydrate (4 mg, 0.03 mmol)were dissolved in DCM (0.8 mL) after which the reaction mixture wasstirred for 10 minutes at RT. Triethylamine (0.09 mL, 0.66 mmol) wasadded dropwise at 0° C. and the reaction mixture warmed to RT andstirred for 18 hrs. The reaction mixture was partitioned between waterand EtOAc and the organics separated, washed with 1 M HCl (aq.),saturated NaHCO₃ (aq.) and brine. The organics were dried via passagethrough a hydrophobic frit and concentrated. The crude material waspurified by flash column chromatography (normal phase) [gradient 0-50%EtOAc in Iso-hexane] to afford methyl 4-((1S)-1-(2-cyclobutyl-2-((4-(trifluoromethyl)benzyl)oxy)acetamido)ethyl)benzoate(82 mg, 0.18 mmol, 69%) as a white solid. LC/MS (Method B): m/z 450[M+H]⁺ (ES⁺), at 1.77 min, UV active.

Step (iv): To a suspension of methyl4-((1S)-1-(2-cyclobutyl-2-((4-(trifluoromethyl)benzyl)oxy)acetamido)ethyl)benzoate(82 mg, 0.18 mmol) in 1,4-dioxane (0.5 mL) and water (0.5 mL) was addedlithium hydroxide monohydrate (30 mg, 0.73 mmol).

The reaction mixture was stirred at RT for 18 hrs then concentrated. Thecrude material was partitioned between 1 M HCl (aq.) and EtOAc and theorganics separated. The aqueous layer was further extracted with EtOAcand the combined organics were dried via passage through a hydrophobicfrit and concentrated. The crude material was purified by flash columnchromatography (normal phase) [gradient 0-6% MeOH in DCM (0.1% aceticacid)]isolating Example 92, racemic4-((1S)-1-(2-cyclobutyl-2-((4-(trifluoromethyl)benzyl)oxy)acetamido)ethyl)benzoicacid as a white solid. Data available in Table 2.

Step (v): Example 92, racemic4-((1S)-1-(2-cyclobutyl-2-((4-(trifluoromethyl)benzyl)oxy)acetamido)ethyl)benzoicacid was separated into single diastereomers via chiral preparative SFC[Phenomenex Lux Amylose-1, 250×21.2 mm, 5 μm] and isocratic conditionsCO₂:EtOH (0.1% NH₃) 80:20 to afford Example 93,4-((1S)-1-(2-cyclobutyl-2-((4-(trifluoromethyl)benzyl)oxy)acetamido)ethyl)benzoicacid (19 mg, 0.04 mmol, 46%) as a white solid and Example 94,4-((1S)-1-(2-cyclobutyl-2-((4-(trifluoromethyl)benzyl)oxy)acetamido)ethyl)benzoicacid (19 mg, 0.04 mmol, 46%) as a white solid. Data available in Table2.

Route Q Procedure for the Preparation of Example 95,4-(1-(2-cyclobutyl-2-((3-(methylsulfonyl)benzyl)oxy)acetamido)cyclopropyl)benzoicacid

Step (i): To an ice cooled solution of intermediate 58, methyl4-(1-(2-cyclobutyl-2-hydroxyacetamido)cyclopropyl)benzoate (150 mg, 0.49mmol) and potassium tert-butoxide (61 mg, 0.54 mmol) in DMF (3.3 mL) wasadded 1-(bromomethyl)-3-methylsulfonyl-benzene (135 mg, 0.54 mmol) andthe reaction mixture warmed to RT and stirred for 18 hrs. The reactionmixture was partitioned between EtOAc and water and the organics wereseparated, washed with brine, dried via passage through a hydrophobicfrit and concentrated. The crude material was purified by reverse phaseHPLC under basic conditions (Gilson Semi Preparative HPLC System,Gemini-NX, 5μ, C18, 100×30 mm) eluted at 40-70% ACN in water with 0.2%of 28% ammonia solution to afford methyl4-(1-(2-cyclobutyl-2-((3-(methylsulfonyl)benzyl)oxy)acetamido)cyclopropyl)benzoate(34 mg, 0.07 mmol, 14%) as a white solid. LC/MS (Method B): m/z 472[M+H]⁺ (ES⁺), at 1.35 min, UV active.

Step (ii): To a suspension of methyl4-(1-(2-cyclobutyl-2-((3-(methylsulfonyl)benzyl)oxy)acetamido)cyclopropyl)benzoate(34 mg, 0.07 mmol) in 1,4-dioxane (0.2 mL) and water (0.2 mL) was addedlithium hydroxide monohydrate (12 mg, 0.29 mmol). The reaction mixturestirred at RT for 18 hrs then concentrated. The crude material waspartitioned between 1 M HCl (aq.) and EtOAc and the organics separated.The aqueous layer was further extracted with EtOAc and the combinedorganics were dried via passage through a hydrophobic frit andconcentrated. The crude material was purified by flash columnchromatography (normal phase) [gradient: 0-6% MeOH in DCM (0.1% aceticacid)] to afford Example 95,4-(1-(2-cyclobutyl-2-((3-(methylsulfonyl)benzyl)oxy)acetamido)cyclopropyl)benzoicacid (20 mg, 0.04 mmol, 60%) as a white solid. Data available in Table2.

Route R Procedure for the Preparation of Example 99,4-(1-(2-cyclobutyl-2-((3-(difluoromethoxy)benzyl)oxy)acetamido)cyclopropyl)benzoicacid, Example 100,(S)-4-(1-(2-cyclobutyl-2-((3-(difluoromethoxy)benzyl)oxy)acetamido)cyclopropyl)benzoicacid, and Example 101,(R)-4-(1-(2-cyclobutyl-2-((3-(difluoromethoxy)benzyl)oxy)acetamido)cyclopropyl)benzoicacid

Step (i): To an ice cooled solution of intermediate 58, methyl4-(1-(2-cyclobutyl-2-hydroxyacetamido)cyclopropyl)benzoate (150 mg, 0.49mmol) and potassium tert-butoxide (61 mg, 0.54 mmol) in DMF (3.3 mL) wasadded 1-(bromomethyl)-3-(difluoromethoxy)benzene (128 mg, 0.54 mmol) andthe reaction mixture warmed to RT and stirred for 18 hrs. The reactionmixture was partitioned between EtOAc and water after which the organicswere separated, washed with brine, dried via passage through ahydrophobic frit and concentrated. The crude material was purified byflash column chromatography (normal phase) [gradient 0-60% EtOAc inIso-hexane] to afford methyl4-(1-(2-cyclobutyl-2-((3-(difluoromethoxy)benzyl)oxy)acetamido)cyclopropyl)benzoate(130 mg, 0.28 mmol, 57%) as a colourless oil. LC/MS (Method B): m/z 460[M+H]⁺ (ES⁺), at 1.62 min, UV active.

Step (ii): To a suspension of methyl4-(1-(2-cyclobutyl-2-((3-(difluoromethoxy)benzyl)oxy)acetamido)cyclopropyl)benzoate(276 mg, 0.60 mmol) in 1,4-dioxane (1.5 mL) and water (1.5 mL) was addedlithium hydroxide monohydrate (100 mg, 2.40 mmol). The reaction mixturestirred at RT for 18 hrs then concentrated. The crude material waspartitioned between 1 M HCl (aq.) and EtOAc and the organics separated.The aqueous layer was further extracted with EtOAc and the combinedorganics were dried via passage through a hydrophobic frit andconcentrated. The crude material was purified by reverse phase HPLCunder basic conditions (Gilson Semi Preparative HPLC System, Gemini-NX,5μ, C18, 100×30 mm) eluted at 15-25% ACN in water with 0.2% of 28%ammonia solution to afford Example 99, racemic4-(1-(2-cyclobutyl-2-((3-(difluoromethoxy)benzyl)oxy)acetamido)cyclopropyl)benzoicacid (146 mg, 0.33 mmol, 54%) as a white solid. Data available in Table2.

Step (iii): Example 99, racemic4-(1-(2-cyclobutyl-2-((3-(difluoromethoxy)benzyl)oxy)acetamido)cyclopropyl)benzoicacid was separated using chiral preparative SFC [Phenomenex LuxAmylose-1, 250×21.2 mm, 5 μm] and isocratic conditions CO₂:IPA 70:30 toafford Example 100,(S)-4-(1-(2-cyclobutyl-2-((3-(difluoromethoxy)benzyl)oxy)acetamido)cyclopropyl)benzoicacid (47 mg, 0.33 mmol, 34%) as a white solid and Example 101,(R)-4-(1-(2-cyclobutyl-2-((3-(difluoromethoxy)benzyl)oxy)acetamido)cyclopropyl)benzoicacid (47 mg, 0.33 mmol, 34%) as a white solid. Data available in Table2. Analytical SFC (Method J) of Example 100 (1.99 min) and Example 101(2.05 min) was used to show this batch of Example 101 prepared usingroute R matched the batch of Example 101 (2.04 min) prepared using routeS.

Route S Alternative Procedure for the Preparation of Example 101,(R)-4-(1-(2-cyclobutyl-2-((3-(difluoromethoxy)benzyl)oxy)acetamido)cyclopropyl)benzoicacid

Step (i): To a solution of 2-amino-2-cyclobutylacetic acid (10.0 g, 77.5mmol) in water (100 mL) and aqueous H₂SO₄ solution (0.5 M, 180 mL) at 0°C. was added sodium nitrite (32 g, 465.1 mmol) and the reaction mixturewarmed to RT and stirred for 16 hrs. The reaction mixture waspartitioned between water and THF. The aqueous layer was four timesfurther extracted with THF. The combined organic layers were dried(Na₂SO₄) and concentrated. The crude residue was washed with EtOAc andthe filtrate concentrated to afford crude 2-cyclobutyl-2-hydroxyaceticacid (8.0 g, 61.5 mmol, 79%) as a yellow liquid. This material was usedwithout further purification.

Step (ii): To a suspension of 2-cyclobutyl-2-hydroxyacetic acid (6.88 g,52.8 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (8.0g, 35.2 mmol) in ACN (70 mL) at 0° C. was added HATU (20.1 g, 52.8 mmol)and allowed to stir at 0° C. for 15 min, after which, DIPEA (18.4 mL,105.7 mmol) was added. The reaction mixture was warmed to RT and stirredfor 16 hrs, then concentrated. The crude residue was purified byreverse-phase gradient flash column chromatography (reverse phase, C18silica), product eluted at 0% to 56% ACN in water to afford methyl4-(1-(2-cyclobutyl-2-hydroxyacetamido) cyclopropyl)benzoate (2.9 g, 9.6mmol, 47%) as a brown solid. LC/MS (Method D): m/z 304 [M+H]⁺ (ES⁺), at1.51 min, UV active.

Step (iii): To a solution of methyl4-(1-(2-cyclobutyl-2-hydroxyacetamido) cyclopropyl)benzoate (5.0 g, 16.5mmol) in DCM (50 mL) was added (R)-2-methoxy-2-phenylacetic acid (3 g,18.14 mmol), N,N′-dicyclohexylcarbodiimide (4.08 g, 19.8 mmol) and DMAP(0.40 g, 3.29 mmol). The reaction mixture was stirred at RT for 16 hrs,then partitioned between water and DCM. The aqueous layer was twice moreextracted with DCM. The combined organics were dried (Na₂SO₄) andconcentrated. The crude residue was purified by normal phase gradientflash column chromatography (Normal phase, silica), product eluted at 0%to 95% diethyl ether in petroleum ether to afford methyl4-(1-((R)-2-cyclobutyl-2-((R)-2-methoxy-2-phenylacetoxy)acetamido)cyclopropyl)benzoate (2.6 g, 5.76 mmol, 35%) as a white solid and methyl4-(1-((S)-2-cyclobutyl-2-((R)-2-methoxy-2-phenylacetoxy)acetamido)cyclopropyl)benzoate (1.0 g, 2.22 mmol, 13%) as a white solid. LC/MS (Method I): m/z453 [M+H]⁺ (ES⁺), at 8.13 min, UV active.

Step (iv): To a solution of methyl4-(1-((R)-2-cyclobutyl-2-((R)-2-methoxy-2-phenylacetoxy)acetamido)cyclopropyl) benzoate (2.6 g, 5.76 mmol) in water (5 mL) and MeOH (5 mL)was added K₂CO₃ (1.19 g, 8.64 mmol) and the resulting solution stirredat RT for 3 hrs. The reaction mixture was partitioned between water andEtOAc and the aqueous layer was twice further extracted with EtOAc. Thecombined organic layers were dried (Na₂SO₄) and concentrated to affordmethyl (R)-4-(1-(2-cyclobutyl-2-hydroxyacetamido)cyclopropyl) benzoate(1.90 g, 6.27 mmol, quantitative) as an off-white solid. LC/MS (MethodD): m/z 304 [M+H]⁺ (ES⁺), at 1.52 min, UV active. Chiral HPLC (Method K)used to determine the stereochemical configuration of R enantiomer(12.06 min) and S enantiomer (10.35 min) by comparison with the known Renantiomer (12.15 min) synthesized using (R)-2-cyclobutylglycine inchiral Route T.

Step (v): Methyl(R)-4-(1-(2-cyclobutyl-2-hydroxyacetamido)cyclopropyl)benzoate (1.9 g,6.26 mmol) was added to a stirred suspension of NaH (˜60% in mineraloil, 0.27 g, 6.89 mmol) in DMF (10 mL) at 0° C. under nitrogenatmosphere. The reaction mixture was stirred at 0° C. for 30 min,followed by addition of 1-(bromomethyl)-3-(difluoromethoxy)benzene (1.78g, 7.54 mmol). The reaction mixture was warmed to RT and stirred for 1hrs, after which it was partitioned between water and EtOAc. The aqueouslayer was twice further extracted with EtOAc. The combined organics weredried (Na₂SO₄) and concentrated. The crude residue was purified byreverse phase gradient flash column chromatography (reverse phase, C18silica), product eluted at 0% to 56% ACN in water to afford methyl(R)-4-(1-(2-cyclobutyl-2-((3-(difluoromethoxy)benzyl)oxy)acetamido)cyclopropyl)benzoate (2.1 g, 4.57 mmol, 73%) as an off whitesolid. LC/MS (Method D): m/z 460 [M+H]⁺ (ES⁺), at 2.27 min, UV active.

Step (vi): To a solution of methyl(R)-4-(1-(2-cyclobutyl-2-((3-(difluoromethoxy) benzyl)oxyacetamido)cyclopropyl)benzoate (2.0 g, 4.35 mmol) in dioxane (5 mL) andwater (3 mL), was added LiOH monohydrate (532 mg, 12.77 mmol). Thereaction mixture was stirred at RT for 4 hrs, then acidified withglacial acetic acid to reach pH ˜4 and concentrated. The crude residuewas purified by reverse phase gradient flash column chromatography(reverse phase, C18 silica), product was eluted at 0% to 58% ACN inwater to afford Example 101,(R)-4-(1-(2-cyclobutyl-2-((3-(difluoromethoxy)benzyl)oxy)acetamido)cyclopropyl)benzoic acid (1.29 g, 2.90 mmol, 67%) as a white solid. Chiral HPLC(Method K) 13.57 min. Data available in table 2.

Route T Additional Alternative Procedure for the Preparation of Example101,(R)-4-(1-(2-cyclobutyl-2-((3-(difluoromethoxy)benzyl)oxy)acetamido)cyclopropyl)benzoicacid

A third route to preparing Example 101 is shown in the scheme aboveusing steps i-iv, analogous to steps i-ii & v-vi shown in route S.Spectroscopic details were consistent with those given for Example 101generated in route S.

General Synthetic Procedures for the Intermediates Route 1 Procedure forthe Preparation of Intermediate 1, methyl4-((S)-1-((R)-2-hydroxy-3-methylbutanamido)ethyl)benzoate

Step (i): To an ice-cooled solution of (2R)-2-hydroxy-3-methyl-butanoicacid (10.0 g, 84.7 mmol) and methyl (S)-4-(1-aminoethyl)benzoate (16.7g, 93.1 mmol) in DMF (170 mL) was added EDC HCl (24.3 g, 127.0 mmol),ethyl (hydroxyimino)cyanoacetate (13.2 g, 93.1 mmol) and triethylamine(29.5 mL, 211.6 mmol). The mixture was stirred at RT for 18 hrs afterwhich it was partitioned between EtOAc and water. The organics wereseparated, washed sequentially with 1 M HCl, sat. aq. NaHCO₃ and brine,dried over MgSO₄ and concentrated to afford Intermediate 1, methyl4-((S)-1-((R)-2-hydroxy-3-methylbutanamido)ethyl)benzoate (12.8 g, 45.9mmol, 54% yield) as an orange solid. Data available in Table 3.

Route 2 Procedure for the Preparation of Intermediate 2, methyl4-((1S)-1-(2-hydroxy-3-methylbutanamido)ethyl)benzoate, and Intermediate3, methyl4-((1S)-1-(3-methyl-2-((methylsulfonyl)oxy)butanamido)ethyl)benzoate

Step (i): To a solution of methyl (S)-4-(1-aminoethyl)benzoate (6.00 g,33.5 mmol) and 2-hydroxy-3-methylbutanoic acid (4.35 g, 36.8 mmol) inDCM (100 mL) were added EDC HCl (9.62 g, 50.2 mmol) and HOBt (900 mg,0.66 mmol). The mixture was stirred at RT for 10 mins after whichtriethylamine (13.5 mL, 100.4 mmol) was added at 0° C. The mixture wasstirred at RT for 4 hrs after which it was partitioned between DCM andsat. aq. NaHCO₃. The organics were separated, and the aqueous layer wasfurther extracted with DCM (×2). The combined organics were dried overNa₂SO₄, concentrated, and the crude material was purified by flashcolumn chromatography (reversed phase, C18) under a gradient of MeCN(0-26%) in water to afford methyl4-((1S)-1-(2-hydroxy-3-methylbutanamido)ethyl)benzoate (6.50 g, 23.3mmol, 70% yield) as a white solid. Data available in Table 3.

Step (ii): To a solution of methyl4-((1S)-1-(2-hydroxy-3-methylbutanamido)ethyl)benzoate (6.70 g, 24.0mmol) and triethylamine (3.52 mL, 26.40 mmol) in DCM (100 mL) at 0° C.was added mesyl chloride (1.8 mL, 24.0 mmol) dropwise. The mixture wasstirred at RT for 2 hrs after which it was partitioned between water andDCM. The organics were separated, and the aqueous layer was furtherextracted with DCM. The combined organics were washed sequentially with1 N HCl then sat. aq. NaHCO₃, dried over Na₂SO₄ and concentrated toafford methyl 4-((1S)-1-(3-methyl-2-((methylsulfonyl)oxy)butanamido)ethyl)benzoate (7.50 g,21.0 mmol, 88% yield) as a white solid. Data available in Table 3.

Route 3 Procedure for the Preparation of Intermediate 4,(R)—N—((S)-1-(4-cyanophenyl) ethyl)-2-hydroxy-3-methylbutanamide

Step (i): To a solution of tert-butyl (S)-(1-(4-cyanophenyl) ethyl)carbamate (1.00 g, 4.06 mmol) in 1,4-dioxane (10 mL) was added 4 N HClin 1,4-dioxane (10 mL). The mixture was stirred at RT for 16 hrs afterwhich it was concentrated under reduced pressure. The crude material wastriturated from 10% EtOAc in Et₂O to afford (S)-4-(1-aminoethyl)benzonitrile hydrochloride (0.57 g, 3.13 mmol, 77% yield) as a yellowsolid. (LC/MS Method D): m/z 147 [M+H−HCl]⁺ (ES⁺), at 0.75 min, UVactive.

Step (ii): To a solution of (R)-2-hydroxy-3-methylbutanoic acid (0.39 g,3.29 mmol) in MeCN (6 mL) was added (S)-4-(1-aminoethyl) benzonitrilehydrochloride (0.50 g, 2.74 mmol) followed by HATU (1.56 g, 4.11 mmol).The mixture was stirred at RT for 30 mins, after which it was cooled to0° C. and N,N-diisopropylethylamine (1.47 mL, 8.23 mmol) was added.

The mixture was stirred at RT for 4 hrs after which it was partitionedbetween EtOAc and water. The organics were separated and the aqueouslayer was further extracted with EtOAc (×2). The combined organics weredried over Na₂SO₄, concentrated, and the crude material was purified byflash column chromatography (reversed phase, C18) under a gradient ofMeCN (0-73%) in water to afford Intermediate 4,(R)—N—((S)-1-(4-cyanophenyl) ethyl)-2-hydroxy-3-methylbutanamide (0.55g, 2.24 mmol, 82% yield) as a sticky brown solid. Data available inTable 3.

Route 4 Procedure for the Preparation of Intermediate 5, methyl(R)-4-(1-(2-hydroxy-3-methylbutanamido)cyclopropyl)benzoate

Step (i): To (2R)-2-hydroxy-3-methyl-butanoic acid (200 mg, 1.69 mmol)in DMF (8.5 mL) was added DIPEA (0.9 mL, 5.08 mmol) and HATU (775 mg,2.03 mmol) followed by methyl 4-(1-aminocyclopropyl)benzoate (356 mg,1.86 mmol). The reaction mixture was stirred for 18 hours at roomtemperature then partitioned between EtOAc and water. The organics wereseparated, washed with brine, dried (phase separator) and concentratedin vacuo. The crude material was purified by flash column chromatography(normal phase) [gradient 0-75% EtOAc in iso-hexane] to affordIntermediate 5, methyl(R)-4-(1-(2-hydroxy-3-methylbutanamido)cyclopropyl)benzoate (212 mg,0.73 mmol, 43%) as a dark orange solid. Data available in Table 3.

Route 5 Procedure for the Preparation of Intermediate 22,4-(bromomethyl)-1-(difluoromethyl)-2-fluorobenzene

Step (i): To a solution of 4-(difluoromethyl)-3-fluorobenzaldehyde (0.50g, 2.87 mmol) in MeOH (3 mL) at 0° C. under an atmosphere of nitrogenwas added NaBH₄ (0.21 g, 5.74 mmol). The mixture was stirred at RT for 1hr after which it was partitioned between EtOAc and water. The organicswere separated, and the aqueous layer was further extracted with EtOAc(×2). The combined organics were dried over Na₂SO₄ and concentrated toafford (4-(difluoromethyl)-3-fluorophenyl) methanol (0.47 g, 2.67 mmol,93% yield) as a colourless liquid. ¹H NMR (400 MHz, DMSO) δ 4.55 (d,J=5.8 Hz, 2H), 5.45 (t, J=5.8 Hz, 1H), 6.97-7.35 (m, 3H), 7.50-7.62 (m,1H).

Step (ii): To a solution of (4-(difluoromethyl)-3-fluorophenyl) methanol(0.25 g, 1.42 mmol) in DCM (3 mL) was added triphenylphosphine (0.55 g,2.13 mmol). The mixture was cooled to 0° C. and tetrabromomethane (0.71g, 2.13 mmol) was added. The mixture was stirred at RT for 1 hr afterwhich it was partitioned between EtOAc and water. The organics wereseparated, and the aqueous layer was further extracted with EtOAc (×2).The combined organics were dried over Na₂SO₄, concentrated, and thecrude material was purified by flash column chromatography (normalphase, silica) under a gradient of EtOAc (0% to 18%) in hexane to affordIntermediate 22, 4-(bromomethyl)-1-(difluoromethyl)-2-fluorobenzene(0.19 g, 0.80 mmol, 56% yield) as a colourless liquid. Data available inTable 3.

Route 6 Procedure for the Preparation of Intermediate 27,2-(bromomethyl)-5-(difluoromethyl)pyridine

Step (i): To a solution of 5-(difluoromethyl)picolinaldehyde (0.30 g,1.91 mmol) in MeOH (3 mL) at 0° C. under an atmosphere of nitrogen wasadded NaBH₄ (0.14 g, 3.82 mmol). The mixture was stirred at RT for 1 hrafter which it was partitioned between EtOAc and water. The organicswere separated, and the aqueous layer was further extracted with EtOAc(×2). The combined organics were dried over Na₂SO₄ and concentrated toafford (5-(difluoromethyl)pyridin-2-yl)methanol (0.30 g, 1.88 mmol, 99%yield) as a colourless liquid. (LC/MS Method D): m/z 160 [M+H]⁺ (ES⁺),at 0.95 min, UV active.

Step (ii): To a solution of phosphorus tribromide (0.36 mL, 3.77 mmol)in DCM (3 mL) at 0° C. was added(5-(difluoromethyl)pyridin-2-yl)methanol (0.30 g, 1.88 mmol). Themixture was stirred at RT for 1 hr after which it was partitionedbetween EtOAc and sat. aq. NaHCO₃. The organics were separated, and theaqueous layer was further extracted with EtOAc (×2). The combinedorganics were dried over Na₂SO₄, concentrated and purified by flashcolumn chromatography (normal phase, silica) under a gradient of EtOAc(0% to 40%) in hexane to afford Intermediate 27,2-(bromomethyl)-5-(difluoromethyl)pyridine (0.17 g, 0.77 mmol, 41%yield) as a yellow liquid. Data available in Table 3.

Route 7 Procedure for the Preparation of Intermediate 32,1-(bromomethyl)-3-(ethylsulfonyl)benzene

Step (i): A suspension of potassium disulphite (3.19 g, 18.3 mmol),tetrabutyl ammonium bromide (2.58 g, 8.01 mmol), sodium formate (1.03 g,15.3 mmol), palladium acetate(II) (85 mg, 0.38 mmol), triphenylphosphine (0.28 g, 1.06 mmol) and 1,10-phenanthroline (0.178 g, 0.99mmol) in DMSO (28 mL) was purged with nitrogen gas at RT for 15 min.Methyl 3-iodobenzoate (2.00 g, 7.60 mmol) was added and the mixture washeated to 100° C. under microwave irradiation for 30 mins. The mixturewas cooled, ethyl iodide (1.00 mL, 12.4 mmol) was added and the mixturewas stirred at RT for 20 mins. The mixture was partitioned between EtOAcand water, the organics were separated, and the aqueous layer wasfurther extracted with EtOAc (×2). The combined organics were dried overNa₂SO₄, concentrated and the residue was purified by flash columnchromatography (reversed phase, C18) under a gradient of MeCN (0-36%) inwater to afford methyl 3-(ethylsulfonyl)benzoate (1.00 g, 4.39 mmol, 57%yield) as a light-yellow sticky liquid. (LC/MS Method H): m/z 229 [M+H]⁺(ES⁺), at 6.98 min, UV active.

Step (ii): To a solution of methyl 3-(ethylsulfonyl)benzoate (1.00 g,4.39 mmol) in THF (10 mL) at −78° C. under an atmosphere of nitrogen wasadded LiAlH₄ (1 M in THF, 6.50 mL) dropwise. The mixture was stirred atthe same temperature for 2 hrs after which it was partitioned betweensat. aq. NH₄Cl and EtOAc. The organics were separated, and the aqueouslayer was further extracted with EtOAc (×2). The combined organics weredried over Na₂SO₄, concentrated under reduced pressure and the residuewas purified by flash column chromatography (reversed phase, C18) undera gradient of MeCN (0-35%) in water to afford (3-(ethylsulfonyl) phenyl)methanol (0.50 g, 2.49 mmol, 57% yield) as a light yellow sticky liquid.(LC/MS Method H): m/z 218 [M+H]⁺ (ES⁺), at 5.56 min, UV active.

Step (iii): To a solution of phosphorus tribromide (0.48 mL, 4.99 mmol)in DCM (5 mL) at 0° C. was added (3-(ethylsulfonyl)phenyl)methanol (0.50g, 2.49 mmol). The mixture was stirred at RT for 1 hr after which it waspartitioned between DCM and sat. aq. NaHCO₃. The organics wereseparated, and the aqueous layer was further extracted with DCM (×2).The combined organics were dried over Na₂SO₄, concentrated and theresidue was purified by flash column chromatography (normal phase,silica) under a gradient of EtOAc (0% to 43%) in hexane to affordIntermediate 32, 1-(bromomethyl)-3-(ethylsulfonyl)benzene (0.24 g, 0.91mmol, 38% yield) as a colourless sticky liquid. Data available in Table3.

Route 8 Procedure for the Preparation of Intermediate 33, methyl4-((S)-1-((R)-2-hydroxy-3-methylbutanamido)ethyl)-2-methylbenzoate

Step (i): Methyl (S)-4-(1-aminoethyl)-2-methylbenzoate hydrochloride(0.15 g, 0.65 mmol) and (R)-2-hydroxy-3-methylbutanoic acid (0.085 g,0.72 mmol) were suspended in ACN (2 mL) at room temperature. HATU (0.37g, 0.98 mmol) was then added at 0° C. and allowed to stir for 15 min.After this time, N, N-diisopropylethylamine (0.34 mL, 1.96 mmol) wasadded at 0° C. and allowed to stir at room temperature for 2 hrs. Thereaction mixture was partitioned between water (15 mL) and EtOAc (20mL). The aqueous layer was further extracted with EtOAc (2×15 mL).Organic layers were combined and dried (Na₂SO₄). Solvent was removed invacuo and the crude product was purified by reverse-phase gradient flashcolumn chromatography (reverse phase, C18 silica), product eluted at 0%to 60% ACN in water to afford pure Intermediate 33, methyl4-((S)-1-((R)-2-hydroxy-3-methylbutanamido)ethyl)-2-methylbenzoate (0.16g, 85%) as sticky oily yellow liquid. Data available in Table 3.

Route 9 Procedure for the Preparation of Intermediate 36,3-(oxetan-3-yl)phenyl)methanol

Step (i): (3-(Methoxycarbonyl)phenyl)boronic acid (2.0 g, 11.07 mmol),3-iodooxetane (4.07 g, 22.1 mmol) and K₂CO₃ (4.58 g, 33.2 mmol) weredissolved in dry 1,4-dioxane (10 mL). Argon gas was purged through themixture at room temperature for 20 min, then Ni(NO₃)₂ hexahydrate (0.161g, 0.55 mmol) and 4,4′-di-tert-butyl-2,2′-dipyridyl (0.14 g, 0.55 mmol)were added and the reaction mixture was heated to 80° C. for 4 hrs. Thereaction mixture was then partitioned between water (250 mL) and EtOAc(250 mL). The aqueous layer was further extracted with EtOAc (2×150 mL).Organic layers were combined and dried (Na₂SO₄), the solvent was removedin vacuo and the crude product was purified by reverse phase gradientflash column chromatography (reverse phase, C18 silica), product elutedat 0% to 46% ACN in water to afford pure methyl 3-(oxetan-3-yl) benzoate(0.58 g, 27%) as a colourless liquid. 1H NMR (400 MHz, DMSO-d₆) δ 3.86(s, 3H), 4.33 (tt, J=8.3, 6.6 Hz, 1H), 4.60 (dd, J=6.6, 6.0 Hz, 2H),4.97 (dd, J=8.3, 6.0 Hz, 2H), 7.54 (t, J=7.7 Hz, 1H), 7.71 (dt, J=7.7,1.3 Hz, 1H), 7.87 (dt, J=7.7, 1.4 Hz, 1H), 7.98 (t, J=1.8 Hz, 1H).

Step (ii): LiAlH₄ (2M in THF) (2.26 mL, 4.52 mmol) was added dropwise toa solution of methyl 3-(oxetan-3-yl)benzoate (0.58 g, 3.01 mmol) in dryTHF (8 mL) under a nitrogen atmosphere at −78° C., and the reactionmixture was allowed to stir at −78° C. for 1 hr. The reaction mixturewas quenched with saturated aqueous NH₄Cl solution (3 mL) thenpartitioned between water (150 mL) and EtOAc (50 mL) and the aqueouslayer was further extracted with EtOAc (2×70 mL). Organic layers werecombined and dried (Na₂SO₄) and the solvent was removed in vacuo toafford crude (3-(oxetan-3-yl)phenyl)methanol (0.43 g, 87%) as acolourless liquid. Data available in Table 3.

Route 10 Procedure for the Preparation of Intermediate 42,7-(chloromethyl)imidazo[1,2-a]pyridine

Step (i): Thionyl chloride (0.2 mL, 3.03 mmol) was added to a solutionof imidazo[1,2-a]pyridin-7-ylmethanol (0.30 g, 2.02 mmol) in CHCl₃ (4mL) under a nitrogen atmosphere at 0° C. and then allowed to stir atroom temperature for 1 hr. The solvent was removed in vacuo and thecrude material was purified by trituration with diethyl ether (3×10 mL)and dried to afford pure Intermediate 42,7-(chloromethyl)imidazo[1,2-a]pyridine (0.31 g, 92%) as a brown solid.Data available in Table 3.

Route 11 Procedure for the Preparation of Intermediate 48,1-(bromomethyl)-3-(cyclopropylsulfonyl)benzene

Step (i): Potassium disulphite (3.19 g, 14.3 mmol), tetrabutyl ammoniumbromide (2.58 g, 8.01 mmol), sodium formate (1.04 g, 15.3 mmol),palladium(II) acetate (0.085 g, 0.38 mmol), triphenylphosphine (0.28 g,1.06 mmol) and 1,10-phenanthroline (0.178 g, 0.99 mmol) were suspendedin DMSO (12 mL) and purged with nitrogen gas at room temperature for 20min. After this time, methyl 3-iodobenzoate (2.00 g, 7.63 mmol) wasadded and reaction mixture was heated to 100° C. in a microwave for 30min. 1-Chloro-3-iodopropane (1.00 mL, 9.31 mmol) was then added at roomtemperature and reaction mixture was allowed to stir at room temperaturefor 16 hrs. The reaction mixture was then partitioned between water (250mL) and EtOAc (250 mL). The aqueous layer was further extracted withEtOAc (2×150 mL) and the combined organic layers were combined and dried(Na₂SO₄). The solvent was removed in vacuo and the crude product waspurified by reverse phase gradient flash column chromatography (reversephase, C18 silica), product eluted at 0% to 57% ACN in water to affordcrude methyl 3-((3-chloropropyl) sulfonyl) benzoate (0.55 g, 26.00%) asbrown sticky liquid. (LC/MS Method H): m/z 277 [M+H]⁺ (ES⁺), at 8.00min, UV active.

Step (ii): Methyl 3-((3-chloropropyl)sulfonyl)benzoate (0.70 g, 2.53mmol) was dissolved in THF (6 mL) under a nitrogen atmosphere at roomtemperature. The reaction mixture was then cooled to 0° C., potassiumtert-butoxide (0.31 g, 2.78 mmol) was added and reaction mixture wasallowed to stir at room temperature for 2.5 hrs. The reaction mixturewas then partitioned between water (150 mL) and EtOAc (200 mL). Theaqueous layer was acidified with 1N aqueous HCl (2.0 mL) to adjust pH to˜3 and the aqueous layer was further extracted with EtOAc (2×150 mL).The organic layers were combined and dried (Na₂SO₄) and the solvent wasremoved in vacuo to afford crude 3-(cyclopropyl)sulfonyl)benzoic acid(0.52 g, 85%) as a yellow solid. (LC/MS Method H): m/z 227 [M+H]⁺ (ES⁺),at 6.86 min, UV active.

Step (iii): 3-(Cyclopropylsulfonyl)benzoic acid (0.50 g, 2.21 mmol) wasdissolved in dry THF (5 mL) under a nitrogen atmosphere at roomtemperature. The reaction mixture was then cooled to 0° C. and BH₃.DMS(0.52 mL, 5.53 mmol) was added dropwise at 0° C. and the reactionmixture was then allowed to stir at room temperature for 16 hrs. Thereaction mixture was then diluted with MeOH (10 mL). The solvent wasremoved in vacuo and the crude product was purified by reverse phasegradient flash column chromatography (reverse phase, C18 silica),product eluted at 0% to 68% ACN in water to afford(3-(cyclopropylsulfonyl)phenyl)methanol (0.17 g, 36%) as a yellow stickyliquid. (LC/MS Method H): m/z 213 [M+H]⁺ (ES⁺), at 5.96 min, UV active.

Step (iv): Phosphorus tribromide (0.14 mL, 1.44 mmol) was dissolved indichloromethane (1 mL) at 0° C. and treated dropwise with a solution of(3-(cyclopropylsulfonyl)phenyl)methanol (0.153 g, 0.72 mmol) in DCM (1mL) at 0° C. and the reaction mixture then allowed to stir at roomtemperature for 0.5 hrs. The reaction mixture was then basified withsaturated NaHCO₃ solution (10 mL) to pH˜8 and partitioned between water(40 mL) and DCM (40 mL). The aqueous layer was further extracted withDCM (2×20 mL) and the organic layers were combined and dried (Na₂SO₄).The solvent was removed in vacuo to afford crude1-(bromomethyl)-3-(cyclopropylsulfonyl)benzene (0.09 g, 46%) as acolorless liquid. Data available in Table 3.

Route 12 Procedure for the Preparation of Intermediate 50,(R)—N-(1-(4-cyanophenyl)cyclopropyl)-2-hydroxy-3-methylbutanamide

Step (i): 1-(4-chlorophenyl) cyclopropane-1-carboxylic acid (55.0 g,0.281 mole) and triethylamine (77.75 mL, 0.561 mole) were dissolved intoluene (250 mL) at room temperature. After this, Diphenylphosphorylazide (66.51 mL, 0.309 mole) and tert-butanol (133.13 mL, 1.403 mole)were added and reaction mixture was stirred at 80° C. for 16h. Reactionmixture was partitioned between water (1000 mL) and DCM (600 mL).Aqueous layer was further extracted with DCM (2×400 mL). Organic layerswere combined and dried (Na₂SO₄). Solvent was removed in vacuo and crudeproduct was purified by gradient flash column chromatography (Normalphase, silica), product eluted at 0% to 10% EtOAc in Hexane to affordtert-butyl (1-(4-chlorophenyl)cyclopropyl)carbamate (60.0 g, 80%) asoff-white solid. (LC/MS Method D): m/z 168.07 (ES+, M-100) at 2.18 min.

Step (ii): tert-butyl (1-(4-chlorophenyl)cyclopropyl)carbamate (20.00 g,74.87 mmole) and Zinc cyanide (13.18 g, 112.31 mmole) were suspended indioxane (45 mL) and nitrogen gas was purged at room temperature for 30min. After this, Bis(tri-tert-butylphosphine) palladium (0) (3.82 g,7.48 mmole) was added at room temperature and reaction mixture wasstirred at 80° C. for 3h. The reaction mixture was partitioned betweenwater (1000 mL) and EtOAc (700 mL) and aqueous layer was furtherextracted with EtOAc (2×300 mL). Organic layers were combined and dried(Na₂SO₄). Solvent was removed in vacuo and crude product was purified bygradient flash column chromatography (Normal phase, silica), producteluted at 0% to 15% EtOAc in Hexane to afford pure tert-butyl(1-(4-cyanophenyl)cyclopropyl)carbamate (11.4 g, 58.98%) as brown solid.Note: Reaction was carried out in 2 divided batches on 10 g scale.(LC/MS Method D): m/z 159 (ES-100), at 1.85 min.

Step (iii): tert-butyl (1-(4-cyanophenyl) cyclopropyl) carbamate (3.00g, 11.62 mmole) was dissolved in dioxane (10 mL) under nitrogenatmosphere. To it, 4N HCl in dioxane (30 mL) was added at roomtemperature and stirred at room temperature for 16h. Solvent was removedin vacuo and crude material was purified by trituration with diethylether (20 mL) to afford 4-(1-aminocyclopropyl) benzonitrilehydrochloride (2.10 g, 93%) as white solid. (LC/MS Method H): m/z 159(ES⁺), at 0.73 min.

Step (iv): (R)-2-hydroxy-3-methylbutanoic acid (1.53 g, 12.98 mmole) wasdissolved in ACN (20 mL) and 4-(1-aminocyclopropyl)benzonitrilehydrochloride (2.10 g, 10.82 mmole) was added to the reaction mixture atroom temperature. After this, HATU (6.17 g, 16.23 mmole) was added andreaction mixture was allowed to stir at room temperature for 30 min.After this, N, N-diisopropylethylamine (5.64 mL, 32.46 mmole) was addedat 0° C. and allowed to stir at room temperature for 1 h. Reactionmixture was concentrated in vacuo to obtain crude product which waspurified by reverse phase gradient flash column chromatography (reversephase, C18 silica), product eluted at 0% to 61% ACN in water to afford(R)—N-(1-(4-cyanophenyl)cyclopropyl)-2-hydroxy-3-methylbutanamideIntermediate 50 (1.80 g, 64.%) as brown solid. Data available in Table3.

Route 13 Procedure for the Preparation of Intermediate 58, methyl4-(1-(2-cyclobutyl-2-hydroxyacetamido)cyclopropyl)benzoate

Step (i): Methyl 4-(1-aminocyclopropyl)benzoate (1.45 g, 7.61 mmol),2-cyclobutyl-2-hydroxy-acetic acid (900 mg, 6.92 mmol), EDC (2.0 g,10.37 mmol) and HOBt monohydrate (93 mg, 0.69 mmol) were dissolved inDCM (21.0 mL) after which the reaction mixture was stirred for 10minutes at RT. Triethylamine (2.4 mL, 17.29 mmol) was added dropwise at0° C. and the reaction mixture stirred for 18 hours at RT. The reactionmixture was partitioned between water and EtOAc and the organicsseparated, washed with 1 M HCl (aq.), saturated NaHCO₃ (aq.) and brine.The organics were separated, dried via passage through a hydrophobicfrit and concentrated to afford Intermediate 58, methyl4-(1-(2-cyclobutyl-2-hydroxyacetamido)cyclopropyl)benzoate (1.5 g, 4.85mmol, 70%) as a light brown solid. The material was used without anyfurther purification. Data available in table 3.

TABLE 2 Synthetic Ex. method & No. Name notes Intermediates ¹H NMR LCMSdata 1 4-((S)-1-((R)-3-methyl-2- Route A 1, 31 ¹H NMR (400 MHz, DMSO) δ0.84 (d, J = 6.8 Hz, 3H), 0.90 (d, J = (LC/MS Method A): m/z 424 ((4-6.8 Hz, 3H), 1.40 (d, J = 7.1 Hz, 3H), 1.88-2.04 (m, 1H), 3.55 [M + H]⁺(ES⁺), at 2.01 min, UV (trifluoromethyl)benzyl)oxy) (d, J = 6.3 Hz, 1H),4.45 (d, J = 12.7 Hz, 1H), 4.64 (d, J = 12.7 active.butanamido)ethyl)benzoic Hz, 1H), 5.00-5.09 (m, 1H), 7.43-7.48 (m, 2H),7.55-7.61 acid (m, 2H), 7.71-7.76 (m, 2H), 7.87-7.92 (m, 2H), 8.43 (d, J= 8.2 Hz, 1H), 12.86 (br.s, 1H). 2 (R)-4-(1-(3-methyl-2-((4- Route B 5,31 ¹H NMR (400 MHz, DMSO) δ 0.88 (d, J = 6.8 Hz, 3H), 0.93 (d, J =(LC/MS Method C): m/z 436 (trifluoromethyl)benzyl)oxy) 6.8 Hz, 3H),1.14-1.32 (m, 4H), 1.95-2.05 (m, 1H), 3.55 (d, [M + H]⁺ (ES⁺), at 2.69min, UV butanamido)cyclopropyl) J = 6.1 Hz, 1H), 4.51 (d, J = 12.7 Hz,1H), 4.69 (d, J = 12.7 Hz, active benzoic acid 1H), 7.22-7.28 (m, 2H),7.58-7.67 (m, 2H), 7.71-7.78 (m, 2H), 7.80-7.87 (m, 2H), 8.78 (s, 1H),12.54 (br.s, 1H). 3 4-((1S)-1-(2-((3- Route E 2, 56 1H-NMR (400 Mz,DMSO) [NB mixture of diastereoisomers] δ (LC/MS Method H): m/z 386methoxybenzyl)oxy)-3- 0.89-0.790 (m, 6H), 1.38 (dd, 3H, J = 2.4 Hz & 7.2Hz), 1.96-1.90 [M + H]⁺ (ES⁺), at 14.17 min and methylbutanamido)ethyl)(m, 1H), 3.50-3.48 (m, 1H), 3.75-3.72 (m, 3H), 4.29 (dd, 1H, J = 14.33min, UV active. benzoic acid, mixture of 4.0 Hz & 12.4 Hz), 4.53-4.48(m, 1H), 5.08-5.00 (m, 1H), 6.91- diastereomers 6.84 (m, 3H), 7.28-7.23(m, 1H), 7.43 (t, 2H, J = 8.8 Hz), 7.87 (dd, 2H, J = 2.0 Hz & 8.4 Hz),8.40-8.36 (m, 1H), 12.87 (s, 1H). 4 4-((S)-1-((S)-2-((4- Route E then 2,24 1H-NMR (400 Mz, DMSO) δ 0.81 (d, J = 6.8 Hz, 3H), 0.86 (d, J = (LC/MSMethod H): m/z 374 fluorobenzyl)oxy)-3- Route G 6.8 Hz, 3H), 1.38 (d, J= 7.1 Hz, 3H), 1.87-1.97 (m, 1H), 3.49 [M + H]⁺ (ES⁺), at 11.48 min, UVmethylbutanamido)ethyl) (d, J = 6.3 Hz, 1H), 4.30 (d, J = 11.7 Hz, 1H),4.49 (d, J = 11.7 active. benzoic acid Hz, 1H), 5.01-5.10 (m, 1H),7.12-7.18 (m, 2H), 7.33-7.39 (m, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.88 (d,J = 8.0 Hz, 2H), 8.39 (d, J = 8.1 Hz, 1H), 12.87 (br.s, 1H). 54-((S)-1-((R)-2-((4- Route C 1, 24 ¹H NMR (400 MHz, DMSO) δ 0.78 (d, J =6.8 Hz, 3H), 0.84 (d, J = (LC/MS Method D): m/z 374 fluorobenzyl)oxy)-3-6.8 Hz, 3H), 1.38 (d, J = 7.1 Hz, 3H), 1.84-1.97 (m, 1H), 3.48 [M + H]⁺(ES⁺), at 2.38 min, UV methylbutanamido)ethyl) (d, J = 6.3 Hz, 1H), 4.31(d, J = 11.7 Hz, 1H), 4.51 (d, J = 11.7 active. benzoic acid Hz, 1H),4.95-5.08 (m, 1H), 7.10-7.23 (m, 2H), 7.33-7.42 (m, 2H), 7.44 (d, J =8.0 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 8.41 (d, J =8.1 Hz, 1H), 12.88(br.s, 1H). 6 4-((1S)-1-(2-((4- Route D 3 ¹H NMR (400 MHz, DMSO) [NBmixture of diastereoisomers] δ (LC/MS Method F): m/z 384methoxybenzyl)oxy)-3- 0.74-0.86 (m, 6H), 1.35-1.42 (m, 3H), 1.83-1.96(m, 1H), [M + H]⁺ (ES⁺), at 4.44 min and methylbutanamido)ethyl)3.42-3.48 (m, 1H), 3.70-3.77 (m, 3H), 4.21-4.28 (m, 1H), 4.53 min, UVactive. benzoic acid, mixture of 4.38-4.50 (m, 1H), 4.94-5.10 (m, 1H),6.84-6.93 (m, 2H), diastereomers 7.17-7.29 (m, 2H), 7.37-7.47 (m, 2H),7.81-7.92 (m, 2H), 8.30-8.38 (m, 1H), 12.89 (br.s, 1H). 74-((S)-1-((S)-3-methyl-2- Route D then 3, 6 ¹H NMR (400 MHz, DMSO) δ0.82 (d, J = 6.7 Hz, 3H), 0.89 (d, J = (LC/MS Method D): m/z 434 ((3-Route G 6.7 Hz, 3H), 1.38 (d, J = 7.1 Hz, 3H), 1.90-2.03 (m, 1H), 3.20[M + H]⁺ (ES⁺), at 2.17 min, UV (methylsulfonyl)benzyl)oxy) (s, 3H),3.55 (d, J = 6.3 Hz, 1H), 4.45 (d, J = 12.4 Hz, 1H), 4.64 active.butanamido)ethyl)benzoic (d, J = 12.4 Hz, 1H), 5.01-5.11 (m, 1H), 7.42(d, J = 8.1 Hz, acid 2H), 7.60-7.71 (m, 2H), 7.83-7.93 (m, 4H), 8.45 (d,J = 8.2 Hz, 1H), 12.78 (br.s, 1H). 8 4-((S)-1-((R)-3-methyl-2- Route C1, 6 ¹H NMR (400 MHz, DMSO) δ 0.82 (d, J = 6.7 Hz, 3H), 0.88 (d, J =(LC/MS Method D): m/z 434 ((3- 6.7 Hz, 3H), 1.38 (d, J = 7.1 Hz, 3H),1.90-2.03 (m, 1H), 3.20 [M + H]⁺ (ES⁺), at 2.04 min, UV(methylsulfonyl)benzyl)oxy) (s, 3H), 3.54 (d, J = 6.3 Hz, 1H), 4.46 (d,J = 12.4 Hz, 1H), 4.65 active. butanamido)ethyl)benzoic (d, J = 12.4 Hz,1H), 4.98-5.09 (m, 1H), 7.44 (d, J = 8.1 Hz, acid 2H), 7.61-7.68 (m,1H), 7.68-7.73 (m, 1H), 7.81-7.93 (m, 4H), 8.46 (d, J = 8.2 Hz, 1H),12.86 (br.s, 1H). 9 4-((S)-1-((S)-3-methyl-2- Route E then 2, 7 ¹H NMR(400 MHz, DMSO) δ 0.84 (d, J = 6.7 Hz, 3H), 0.89 (d, J = (LC/MS MethodD): m/z 434 ((4- Route G 6.7 Hz, 3H), 1.39 (d, J = 7.1 Hz, 3H),1.90-2.02 (m, 1H), 3.19 [M + H]⁺ (ES⁺), at 2.07 min, UV(methylsulfonyl)benzyl)oxy) (s, 3H), 3.55 (d, J = 6.3 Hz, 1H), 4.45 (d,J = 12.9 Hz, 1H), 4.63 active. butanamido)ethyl)benzoic (d, J = 12.9 Hz,1H), 5.01-5.12 (m, 1H), 7.43 (d, J = 8.0 Hz, acid 2H), 7.60 (d, J = 8.0Hz, 2H), 7.84-7.95 (m, 4H), 8.47 (d, J = 8.1 Hz, 1H), 12.87 (br.s, 1H).10 4-((S)-1-((R)-3-methyl-2- Route C 1, 7 ¹H NMR (400 MHz, DMSO) δ 0.82(d, J = 6.7 Hz, 3H), 0.88 (d, J = (LC/MS Method D): m/z 434 ((4- 6.7 Hz,3H), 1.38 (d, J = 7.1 Hz, 3H), 1.86-2.01 (m, 1H), 3.20 [M + H]⁺ (ES⁺),at 2.07 min, UV (methylsulfonyl)benzyl)oxy) (s, 3H), 3.54 (d, J = 6.3Hz, 1H), 4.44 (d, J = 12.9 Hz, 1H), 4.64 active.butanamido)ethyl)benzoic (d, J = 12.9 Hz, 1H), 4.95-5.12 (m, 1H), 7.45(d, J = 8.0 Hz, acid 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.84-7.96 (m, 4H),8.48 (d, J = 8.1 Hz, 1H), 12.89 (br.s, 1H). 11 4-((S)-1-((R)-2-((4-Route E 1 ¹H NMR (400 MHz, DMSO) δ 0.79 (d, J = 6.7 Hz, 3H), 0.85 (d, J= (LC/MS Method D): m/z 390 chlorobenzyl)oxy)-3- 6.7 Hz, 3H), 1.38 (d, J= 7.1 Hz, 3H), 1.83-2.02 (m, 1H), 3.49 [M + H]⁺ (ES⁺), at 2.48 min, UVmethylbutanamido)ethyl) (d, J = 6.3 Hz, 1H), 4.32 (d, J = 12.2 Hz, 1H),4.52 (d, J = 12.2 active. benzoic acid Hz, 1H), 4.95-5.09 (m, 1H),7.33-7.46 (m, 6H), 7.88 (d, J = 8.3 Hz, 2H), 8.40 (d, J = 8.1 Hz, 1H),12.86 (br.s, 1H). 12 4-((S)-1-((R)-2-((3- Route E 1, 8 ¹H NMR (400 MHz,DMSO) δ 0.81 (d, J = 6.7 Hz, 3H), 0.86 (d, J= (LC/MS Method D): m/z 390chlorobenzyl)oxy)-3- 6.7 Hz, 3H), 1.38 (d, J = 7.0 Hz, 3H), 1.83-1.99(m, 1H), 3.50 [M + H]⁺ (ES⁺), at 2.46 min, UV methylbutanamido)ethyl)(d, J = 6.2 Hz, 1H), 4.35 (d, J = 12.3 Hz, 1H), 4.54 (d, J = 12.3active. benzoic acid Hz, 1H), 4.96-5.08 (m, 1H), 7.26-7.47 (m, 6H), 7.87(d, J = 7.9 Hz, 2H), 8.41 (d, J = 8.2 Hz, 1H), 13.12 (br.s, 1H). 134-((S)-1-((R)-2-((4- Route F 1, 49 ¹H NMR (400 MHz, DMSO) δ 0.81 (d, J =6.6 Hz, 3H), 0.87 (d, J = (LC/MS Method D): m/z 406(difluoromethyl)benzyl)oxy)- 6.6 Hz, 3H), 1.38 (d, J = 6.9 Hz, 3H),1.84-2.01 (m, 1H), 3.51 [M + H]⁺ (ES⁺), at 2.36 min, UV 3- (d, J = 6.2Hz, 1H), 4.39 (d, J = 12.4 Hz, 1H), 4.59 (d, J = 12.4 active.methylbutanamido)ethyl) Hz, 1H), 4.95-5.10 (m, 1H), 7.02 (t, J = 56 Hz,1H), 7.38-7.51 benzoic acid (m, 4H), 7.53-7.59 (m, 2H), 7.84-7.93 (m,2H), 8.42 (d, J = 8.2 Hz, 1H), 12.92 (br.s, 1H). 14 4-((S)-1-((R)-2-((3-Route E 1, 9 ¹H NMR (400 MHz, DMSO) δ 0.86 (d, J = 6.7 Hz, 3H), 0.92 (d,J = (LC/MS Method G): m/z 406 (difluoromethyl)benzyl)oxy)- 6.7 Hz, 3H),1.43 (d, J = 7.1 Hz, 3H), 1.92-2.06 (m, 1H), 3.56 [M + H]⁺ (ES⁺), at4.70 min, UV 3- (d, J = 6.2 Hz, 1H), 4.44 (d, J = 12.2 Hz, 1H), 4.65 (d,J = 12.2 active. methylbutanamido)ethyl) Hz, 1H), 4.99-5.17 (m, 1H),7.08 (t, J = 56 Hz, 1H), 7.50 (d, J = benzoic acid 7.9 Hz, 2H), 7.58 (s,4H), 7.93 (d, J = 7.9 Hz, 2H), 8.48 (d, J = 8.1 Hz, 1H), 12.92 (br.s,1H). 15 4-((S)-1-((R)-3-methyl-2- Route E 1, 10 ¹H NMR (400 MHz, DMSO) δ0.86 (d, J = 6.7 Hz, 3H), 0.92 (d, J = (LC/MS Method D): m/z 424 ((3-6.7 Hz, 3H), 1.43 (d, J = 7.1 Hz, 3H), 1.94-2.06 (m, 1H), 3.58 [M + H]⁺(ES⁺), at 2.50 min, UV (trifluoromethyl)benzyl)oxy) (d, J = 6.3 Hz, 1H),4.49 (d, J = 12.5 Hz, 1H), 4.68 (d, J = 12.5 active.butanamido)ethyl)benzoic Hz, 1H), 5.02-5.12 (m, 1H), 7.47-7.51 (m, 2H),7.59-7.79 acid (m, 4H), 7.89-7.96 (m, 2H), 8.50 (d, J = 8.2 Hz, 1H),12.92 (br.s, 1H). 16 4-((S)-1-((S)-3-methyl-2- Route C 31 1H NMR (400MHz, DMSO-d6) δ 12.61 (br s, 1H), 8.43 (d, J = (LC/MS Method C): m/z 424((4- 8.2 Hz, 1H), 7.91-7.87 (m, 2H), 7.74-7.69 (m, 2H), 7.59- [M + H]⁺(ES⁺), at 2.60 min, UV (trifluoromethyl)benzyl)oxy) 7.54 (m, 2H),7.46-7.42 (m, 2H), 5.12-5.03 (m, 1H), 4.63 (d, J = active.butanamido)ethyl)benzoic 12.8 Hz, 1H), 4.45 (d, J = 12.8 Hz, 1H), 3.56(d, J = 6.1 Hz, acid 1H), 2.03-1.94 (m, 1H), 1.40 (d, J = 7.1 Hz, 3H),0.91 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H). 17 4-((1S)-1-(2-((3-Route E then 2, 11 ¹H NMR (400 MHz, DMSO) δ 0.80 (d, J = 6.7 Hz, 3H),0.86 (d, J = (LC/MS Method H): m/z 374 fluorobenzyl)oxy)-3- Route G 6.7Hz, 3H), 1.38 (d, J = 7.1 Hz, 3H), 1.83-2.01 (m, 1H), 3.50 [M + H]⁺(ES⁺), at 9.26 min, UV methylbutanamido)ethyl) (d, J = 6.6 Hz, 1H), 4.36(d, J = 12.3 Hz, 1H), 4.54 (d, J = 12.3 active benzoic acid,diastereomer 1 Hz, 1H), 4.93-5.08 (m, 1H), 7.05-7.24 (m, 3H), 7.32-7.49(m, 3H), 7.87 (d, J = 7.8 Hz, 2H), 8.41 (d, J = 8.2 Hz, 1H), 12.85(br.s, 1H). 18 4-((1S)-1-(2-((3- Route E then 2, 11 ¹H NMR (400 MHz,DMSO) δ 0.83 (d, J = 6.7 Hz, 3H), 0.88 (d, J = (LC/MS Method H): m/z 374fluorobenzyl)oxy)-3- Route G 6.7 Hz, 3H), 1.39 (d, J = 7.1 Hz, 3H),1.82-2.02 (m, 1H), 3.52 [M + H]⁺ (ES⁺), at 9.37 min, UVmethylbutanamido)ethyl) (d, J = 6.1 Hz, 1H), 4.35 (d, J = 12.3 Hz, 1H),4.53 (d, J = 12.3 active benzoic acid, diastereomer 2 Hz, 1H), 5.00-5.12(m, 1H), 7.07-7.21 (m, 3H), 7.34-7.49 (m, 3H), 7.87 (d, J = 8.0 Hz, 2H),8.41 (d, J = 8.2 Hz, 1H), 12.87 (br.s, 1H). 194-((S)-1-((R)-2-(benzyloxy)- Route E 1, 12 ¹H NMR (400 MHz, DMSO) δ 0.79(d, J = 6.7 Hz, 3H), 0.85 (d, J = (LC/MS Method D): m/z 356 3- Step (i):1.2 6.7 Hz, 3H), 1.38 (d, J = 7.0 Hz, 3H), 1.84-1.99 (m, 1H), 3.49 [M +H]⁺ (ES⁺), at 2.32 min, UV methylbutanamido)ethyl) equivalents of (d, J= 6.3 Hz, 1H), 4.32 (d, J = 11.9 Hz, 1H), 4.54 (d, J = 11.9 active.benzoic acid both NaH and Hz, 1H), 4.96-5.09 (m, 1H), 7.25-7.39 (m, 5H),7.45 (d, J = alkylating 8.3 Hz, 2H), 7.88 (d, J = 8.3 Hz, 2H), 8.39 (d,J = 8.1 Hz, 1H), reagent used 12.87 (br.s, 1H). 204-((S)-1-((R)-3-methyl-2- Route F 1, 13 ¹H NMR (400 MHz, DMSO) δ 0.80(d, J = 6.7 Hz, 3H), 0.86 (d, J = (LC/MS Method D): m/z 440 ((3- 6.7 Hz,3H), 1.38 (d, J = 7.1 Hz, 3H), 1.88-2.02 (m, 1H), 3.51 [M + H]⁺ (ES⁺),at 2.56 min, UV (trifluoromethoxy)benzyl) (d, J = 6.2 Hz, 1H), 4.39 (d,J = 12.5 Hz, 1H), 4.59 (d, J = 12.5 active. oxy)butanamido)ethyl) Hz,1H), 4.92-5.12 (m, 1H), 7.26-7.38 (m, 3H), 7.41-7.53 benzoic acid (m,3H), 7.88 (d, J = 8.0 Hz, 2H), 8.44 (d, J = 8.2 Hz, 1H), 12.87 (br.s,1H). 21 4-((S)-1-((R)-2-((4- Route C 1, 14 ¹H NMR (400 MHz, DMSO) δ 0.82(d, J = 6.7 Hz, 3H), 0.88 (d, J = (LC/MS Method D): m/z 381cyanobenzyl)oxy)-3- Step (i): 1.5 6.7 Hz, 3H), 1.38 (d, J = 7.1 Hz, 3H),1.87-2.02 (m, 1H), 3.53 [M + H]⁺ (ES⁺), at 2.20 min, UVmethylbutanamido)ethyl) equivalents of (d, J = 6.3 Hz, 1H), 4.43 (d, J =13.1 Hz, 1H), 4.62 (d, J = 13.1 active. benzoic acid alkylating Hz, 1H),4.97-5.08 (m, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.55 (d, J = reagent used8.0 Hz, 2H), 7.82 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.1 Hz, 2H), 8.45(d, J = 8.1 Hz, 1H), 12.85 (br.s, 1H). 22 4-((S)-1-((R)-2-((3- Route C1, 15 ¹H NMR (400 MHz, DMSO) δ 0.81 (d, J = 6.7 Hz, 3H), 0.86 (d, J=(LC/MS Method D): m/z 381 cyanobenzyl)oxy)-3- Step (i): 1.5 6.7 Hz, 3H),1.38 (d, J = 7.1 Hz, 3H), 1.86- 1.99 (m, 1H), 3.52 [M + H]⁺ (ES⁺), at2.21 min, UV methylbutanamido)ethyl) equivalents of (d, J = 6.2 Hz, 1H),4.41 (d, J = 12.4 Hz, 1H), 4.57 (d, J = 12.4 active. benzoic acidalkylating Hz, 1H), 4.94-5.09 (m, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.57(dd, reagent used J = 7.8 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.77 (d, J= 7.8 Hz, 1H), 7.81 (s, 1H), 7.88 (d, J = 8.1 Hz, 2H), 8.43 (d, J = 8.2Hz, 1H), 12.85 (br.s, 1H). 23 4-((S)-1-((R)-2-((4- Route C 1, 16 ¹H NMR(400 MHz, DMSO) δ 0.79 (d, J = 6.7 Hz, 3H), 0.84 (d, J = (LC/MS MethodD): m/z 422 (difluoromethoxy)benzyl) Step (i): 1.3 6.7 Hz, 3H), 1.38 (d,J = 7.1 Hz, 3H), 1.84- 1.99 (m, 1H), 3.49 [M + H]⁺ (ES⁺), at 2.39 min,UV oxy)-3-methylbutanamido) equivalents of (d, J = 6.3 Hz, 1H), 4.32 (d,J = 11.9 Hz, 1H), 4.52 (d, J = 11.9 active. ethyl)benzoic acidalkylating Hz, 1H), 4.94-5.08 (m, 1H), 6.99-7.42 (m, 5H), 7.44 (d, J =reagent used 8.1 Hz, 2H), 7.88 (d, J = 8.1 Hz, 2H), 8.40 (d, J = 8.1 Hz,1H), 12.87 (br.s, 1H). 24 4-((S)-1-((R)-2-((3- Route C 1, 17 NMR (400MHz, DMSO) δ 0.81 (d, J = 6.7 Hz, 3H), 0.86 (d, J = (LC/MS Method D):m/z 422 (difluoromethoxy)benzyl) Step (i): 1.5 6.7 Hz, 3H), 1.38 (d, J =7.0 Hz, 3H), 1.87-2.00 (m, 1H), 3.51 [M + H]⁺ (ES⁺), at 2.39 min, UVoxy)-3-methylbutanamido) equivalents of (d, J = 6.2 Hz, 1H), 4.35 (d, J= 12.4 Hz, 1H), 4.56 (d, J = 12.4 active. ethyl)benzoic acid alkylatingHz, 1H), 4.95-5.10 (m, 1H), 7.00-7.47 (m, 7H), 7.88 (d, J = reagentused; 8.0 Hz, 2H), 8.41 (d, J =8.1 Hz, 1H), 12.87 (br.s, 1H). 1.3equivalents NaH used 25 4-((S)-1-((R)-3-methyl-2- Route C 1, 18 ¹H NMR(400 MHz, DMSO) δ 0.79-0.94 (m, 6H), 1.38 (d, J = (LC/MS Method D): m/z425 ((5-(trifluoromethyl)pyridin- Step (i): 1.5 7.0 Hz, 3H), 1.93-2.07(m, 1H), 3.66 (d, J = 5.9 Hz, 1H), 4.59 [M + H]⁺ (ES⁺), at 2.32 min, UV2-yl)methoxy)butanamido) equivalents of (d, J = 13.9 Hz, 1H), 4.70 (d, J= 13.9 Hz, 1H), 4.94-5.11 (m, active. ethyl)benzoic acid alkylating 1H),7.42 (d, J = 7.9 Hz, 2H), 7.72 (d, J = 8.3 Hz, 1H), 7.87 (d, J = reagentused; 7.9 Hz, 2H), 8.24 (dd, J = 8.3, 2.3 Hz, 1H), 8.59 (d, J = 8.1 Hz,1.2 1H), 8.91 (s, 1H), 12.98 (br.s, 1H). equivalents NaH used 264-((S)-1-((R)-3-methyl-2- Route C 1, 19 ¹H NMR (400 MHz, DMSO) δ 0.83(d, J = 6.7 Hz, 3H), 0.88 (d, J = (LC/MS Method D): m/z 482((4-(pentafluoro-λ6- Step (i): 1.5 6.7 Hz, 3H), 1.37 (d, J = 7.0 Hz,3H), 1.85-2.06 (m, 1H), 3.54 [M + H]⁺ (ES⁺), at 2.63 min, UVsulfaneyl)benzyl)oxy) equivalents of (d, J = 6.2 Hz, 1H), 4.43 (d, J =13.0 Hz, 1H), 4.62 (d, J = 13.0 active. butanamido)ethyl)benzoicalkylating Hz, 1H), 4.96-5.09 (m, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.57(d, J = acid reagent used; 8.3 Hz, 2H), 7.84-7.92 (m, 4H), 8.44 (d, J =8.2 Hz, 1H), 1.1 12.87 (br.s, 1H). equivalents NaH used 274-((S)-1-((R)-2-((3,4- Route C 1, 20 ¹H NMR (400 MHz, DMSO) δ 0.80 (d, J= 6.6 Hz, 3H), 0.85 (d, J = (LC/MS Method D): m/z 392difluorobenzyl)oxy)-3- Step (i): 1.3 6.6 Hz, 3H), 1.38 (d, J = 7.0 Hz,3H), 1.87- 1.99 (m, 1H), 3.50 [M + H]⁺ (ES⁺), at 2.40 min, UVmethylbutanamido)ethyl) equivalents of (d, J = 6.1 Hz, 1H), 4.34 (d, J =12.2 Hz, 1H), 4.50 (d, J = 12.2 active. benzoic acid alkylating Hz, 1H),4.95-5.09 (m, 1H), 7.14-7.23 (m, 1H), 7.36-7.47 reagent used; (m, 4H),7.87 (d, J = 8.0 Hz, 2H), 8.41 (d, J = 8.1 Hz, 1H), 12.91 1.5 (s,1H).equivalents NaH used 28 4-((S)-1-((R)-2-((2,2- Route C 1, 21 ¹H NMR (400MHz, DMSO) δ 0.80 (d, J = 6.7 Hz, 3H), 0.84 (d, J = (LC/MS Method D):m/z 436 difluorobenzo[d][1,3]dioxol- 6.7 Hz, 3H), 1.37 (d, J = 7.0 Hz,3H), 1.85- 1.99 (m, 1H), 3.50 [M + H]⁺ (ES⁺), at 2.55 min, UV5-yl)methoxy)-3- (d, J = 6.1 Hz, 1H), 4.36 (d, J = 12.0 Hz, 1H), 4.52(d, J = 12.0 active. methylbutanamido)ethyl) Hz, 1H), 4.93-5.07 (m, 1H),7.14-7.21 (m, 1H), 7.36-7.47 benzoic acid (m, 4H), 7.85-7.91 (m, 2H),8.38 (d, J = 8.2 Hz, 1H), 12.86 (br.s, 1H). 29 4-((S)-1-((R)-2-((4-Route C 1, 22 ¹H NMR (400 MHz, DMSO) δ 0.82 (d, J = 6.7 Hz, 3H), 0.88(d, J = (LC/MS Method D): m/z 424 (difluoromethyl)-3- Step (i): 1.5 6.7Hz, 3H), 1.38 (d, J = 7.0 Hz, 3H), 1.83-2.01 (m, 1H), 3.53 [M + H]⁺(ES⁺), at 2.43 min, UV fluorobenzyl)oxy)-3- equivalents of (d, J = 6.2Hz, 1H), 4.42 (d, J = 13.0 Hz, 1H), 4.59 (d, J = 13.0 active.methylbutanamido)ethyl) alkylating Hz, 1H), 4.93-5.10 (m, 1H), 7.01-7.37(m, 3H), 7.44 (d, J = benzoic acid reagent used 8.0 Hz, 2H), 7.58-7.65(m, 1H), 7.88 (d, J = 8.0 Hz, 2H), 8.43 (d, J = 8.2 Hz, 1H), 12.86(br.s, 1H). 30 4-((S)-1-((R)-2-((4- Route C 1, 23 ¹H NMR (400 MHz, DMSO)δ 0.59-0.68 (m, 2H), 0.78 (d, J = (LC/MS Method D): m/z 396cyclopropylbenzyl)oxy)-3- Step (i): 1.5 6.7 Hz, 3H), 0.83 (d, J = 6.7Hz, 3H), 0.88-0.98 (m, 2H), 1.37 [M + H]⁺ (ES⁺), at 2.60 min, UVmethylbutanamido)ethyl) equivalents of (d, J = 7.0 Hz, 3H), 1.80-1.99(m, 2H), 3.45 (d, J = 6.2 Hz, 1H), active. benzoic acid alkylating 4.26(d, J = 11.7 Hz, 1H), 4.47 (d, J = 11.7 Hz, 1H), 4.92-5.07 reagent used(m, 1H), 7.04 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 7.8 Hz, 2H), 7.43 (d, J= 8.0 Hz, 2H), 7.87 (d, J = 8.0 Hz, 2H), 8.35 (d, J = 8.1 Hz, 1H), 12.87(br.s, 1H). 31 (R)-4-(1-(2-((4- Route E 5, 24 ¹H NMR (400 MHz, DMSO) δ0.76-0.94 (m, 6H), 1.07-1.37 (LC/MS Method D): m/z 386fluorobenzyl)oxy)-3- (m, 5H), 3.49 (d, J = 6.0 Hz, 1H), 4.38 (d, J =12.0 Hz, 1H), 4.56 [M + H]⁺ (ES⁺), at 2.54 min, UV methylbutanamido) (d,J = 12.0 Hz, 1H), 7.08-7.27 (m, 4H), 7.37-7.49 (m, 2H), active.cyclopropyl)benzoic acid 7.76-7.86 (m, 2H), 8.74 (s, 1H), 12.86 (br.s,1H). 32 4-((S)-1-((R)-2-((3- Route E 1,25 ¹H NMR (400 MHz, DMSO) δ 0.79(d, J = 6.7 Hz, 3H), 0.85 (d, J = (LC/MS Method D): m/z 440(difluoromethoxy)-4- Step (i): 1.2 6.7 Hz, 3H), 1.37 (d, J = 7.1 Hz,3H), 1.84- 1.99 (m, 1H), 3.49 [M + H]⁺ (ES⁺), at 2.41 min, UVfluorobenzyl)oxy)-3- equivalents of (d, J = 6.3 Hz, 1H), 4.32 (d, J =12.1 Hz, 1H), 4.51 (d, J = 12.1 active. methylbutanamido)ethyl) NaH usedHz, 1H), 4.91-5.10 (m, 1H), 7.00-7.46 (m, 6H), 7.87 (d, J = benzoic acid8.0 Hz, 2H), 8.42 (d, J = 8.2 Hz, 1H), 12.85 (br.s, 1H). 33(R)-4-(1-(3-methyl-2-((3- Route C 5, 6 ¹H NMR (400 MHz, DMSO) δ 0.85 (d,J = 6.7 Hz, 3H), 0.90 (d, J = (LC/MS Method D): m/z 446(methylsulfonyl)benzyl)oxy) 6.7 Hz, 3H), 1.08-1.33 (m, 4H), 1.91-2.05(m, 1H), 3.18 (s, [M + H]⁺ (ES⁺), at 2.06 min, UVbutanamido)cyclopropyl) 3H), 3.53 (d, J = 6.1 Hz, 1H), 4.50 (d, J = 12.5Hz, 1H), 4.69 (d, active. benzoic acid J = 12.5 Hz, 1H), 7.16-7.24 (m,2H), 7.59-7.68 (m, 1H), 7.69- 7.76 (m, 1H), 7.79-7.88 (m, 3H), 7.93 (s,1H), 8.80 (s, 1H), 12.77 (br.s, 1H). 34 4-((S)-1-((R)-2-((5- Route C 1,27 ¹H NMR (400 MHz, DMSO) δ 0.78-0.89 (m, 6H), 1.37 (d, J = (LC/MSMethod E): m/z 407 (difluoromethyl)pyridin-2- Step (i): 1.5 7.0 Hz, 3H),1.91-2.03 (m, 1H), 3.64 (d, J = 5.7 Hz, 1H), 4.55 [M + H]⁺ (ES⁺), at2.00 min, UV yl)methoxy)-3- equivalents of (d, J = 13.5 Hz, 1H), 4.66(d, J = 13.5 Hz, 1H), 4.96-5.06 (m, active. methylbutanamido)ethyl)alkylating 1H), 7.14 (t, J = 55 Hz, 1H), 7.44 (d, J = 7.9 Hz, 2H), 7.63(d, J = benzoic acid reagent used 8.1 Hz, 1H), 7.87 (d, J = 7.9 Hz, 2H),8.03 (d, J = 8.1 Hz, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.72 (s, 1H), 12.86(br.s, 1H). 35 4-((S)-1-((R)-2-((4-fluoro-3- Route C 1, 28 ¹H NMR (400MHz, DMSO) δ 0.80 (d, J = 6.6 Hz, 3H), 0.86 (d, J = (LC/MS Method D):m/z 452 (methylsulfonyl)benzyl)oxy)- Step (i): 1.5 6.6 Hz, 3H), 1.38 (d,J = 7.0 Hz, 3H), 1.84-2.09 (m, 1H), 3.31 [M + H]⁺ (ES⁺), at 2.19 min, UV3- equivalents of (s, 3H), 3.52 (d, J = 6.3 Hz, 1H), 4.41 (d, J = 12.4Hz, 1H), 4.59 active. methylbutanamido)ethyl) alkylating (d, J = 12.4Hz, 1H), 4.92-5.08 (m, 1H), 7.43 (d, J = 8.0 Hz, benzoic acid reagentused 2H), 7.48-7.53 (m, 1H), 7.69-7.77 (m, 1H), 7.81-7.91 (m, 3H), 8.44(d, J = 8.1 Hz, 1H), 12.84 (br.s, 1H). 36 2-methyl-4-((S)-1-((R)-3-Route E 31, 33 ¹H NMR (400 MHz, Methanol-da) δ 0.92 and 0.96 (2 xd, J =6.8 (LC/MS Method D): m/z 438 methyl-2-((4- Step (i): 1.2 Hz, 6H), 1.46(d, J = 7.0 Hz, 3H), 2.03 (h, J = 6.7 Hz, 1H), 2.57 [M + H]⁺ (ES⁺), at2.64 min, UV (trifluoromethyl)benzyl)oxy) equivalents of (s, 3H), 3.58(d, J = 6.1 Hz, 1H), 4.49 (d, J = 12.4 Hz, 1H), 4.69 active.butanamido)ethyl)benzoic NaH used (d, J = 12.5 Hz, 1H), 5.00-5.12 (m,1H), 7.20-7.31 (m, 2H), acid 7.55 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 7.9Hz, 2H), 7.88 (d, J = 8.0 Hz, 1H), 8.48 (d, J = 8.2 Hz, 1H). 37(R)-4-(1-(2-((3,4- Route C 5, 20 ¹H NMR (400 MHz, DMSO) δ 0.78-0.93 (m,6H), 1.12-1.32 (LC/MS Method D): m/z 404 difluorobenzyl)oxy)-3- (m, 4H),1.87-2.02 (m, 1H), 3.49 (d, J = 6.0 Hz, 1H), 4.39 (d, J = [M + H]⁺(ES⁺), at 2.53 min, UV methylbutanamido) 12.2 Hz, 1H), 4.54 (d, J = 12.2Hz, 1H), 7.14-7.28 (m, 3H), active. cyclopropyl)benzoic acid 7.37-7.49(m, 2H), 7.81 (d, J = 8.0 Hz, 2H), 8.73 (s, 1H), 12.79 (br.s, 1H). 384-((S)-1-((R)-2-((3- Route E 1, 37 1H NMR (400 MHz, DMSO-d6) δ 0.81 (d,J = 6.8 Hz, 3H), 0.86 (LC/MS Method D): m/z 372 hydroxybenzyl)oxy)-3-Step (i): 1.1 (d, J = 6.7 Hz, 3H), 1.39 (d, J = 7.0 Hz, 3H), 1.93 (h, J= 6.6 Hz, [M + H]⁺ (ES⁺), at 2.02 min, UV methylbutanamido)ethyl)equivalents of 1H), 3.48 (d, J = 6.3 Hz, 1H), 4.24 (d, J = 12.0 Hz, 1H),4.47 (d, active. benzoic acid NaH used, J = 12.0 Hz, 1H), 5.02 (q, J =7.4 Hz, 1H), 6.65-6.80 (m, 3H), then Route L 7.13 (t, J = 7.8 Hz, 1H),7.45 (d, J = 8.0 Hz, 2H), 7.89 (d, J = 8.0 Hz, 2H), 8.36 (d, J = 8.1 Hz,1H), 9.39 (s, 1H). 39 4-((S)-1-((R)-2-((3- Route E 1, 29 ¹H NMR (400MHz, DMSO) δ 0.53-0.67 (m, 2H), 0.70-0.97 (LC/MS Method D): m/z 396cyclopropylbenzyl)oxy)-3- Step (i): 1.2 (m, 8H), 1.37 (d, J = 7.2 Hz,3H), 1.78-2.00 (m, 2H), 3.46 (d, J = [M + H]⁺ (ES⁺), at 2.54 min, UVmethylbutanamido)ethyl) equivalents of 6.4 Hz, 1H), 4.27 (d, J = 11.9Hz, 1H), 4.48 (d, J = 11.9 Hz, active. benzoic acid NaH used 1H),4.93-5.07 (m, 1H), 6.93-7.03 (m, 2H), 7.03-7.12 (m, 1H), 7.16-7.25 (m,1H), 7.31-7.50 (m, 2H), 7.79-7.94 (m, 2H), 8.34 (d, J = 8.2 Hz, 1H),12.85 (br.s, 1H). 40 4-((S)-1-((R)-2-((3- Route E 1, 30 ¹H NMR (400 MHz,DMSO) δ 0.78 (d, J = 6.7 Hz, 3H), 0.84 (d, J = (LC/MS Method E): m/z 400(methoxymethyl)benzyl) Step (i): 1.2 6.7 Hz, 3H), 1.37 (d, J = 7.1 Hz,3H), 1.82- 1.99 (m, 1H), 3.26 [M + H]⁺ (ES⁺), at 1.99 min, UV oxy)-3-equivalents of (s, 3H), 3.48 (d, J = 6.3 Hz, 1H), 4.31 (d, J = 11.9 Hz,1H), 4.38 active. methylbutanamido)ethyl) NaH used (s, 2H), 4.53 (d, J =11.9 Hz, 1H), 4.87-5.11 (m, 1H), 7.18- benzoic acid 7.37 (m, 4H),7.41-7.48 (m, 2H), 7.81-7.95 (m, 2H), 8.37 (d, J = 8.2 Hz, 1H), 12.88(br.s, 1H). 41 4-((S)-1-((R)-2-((4- Route E 1, 38 1H NMR (400 MHz,DMSO-d6) δ 0.77 (d, J = 6.8 Hz, 3H), 0.82 (LC/MS Method D): m/z 372hydroxybenzyl)oxy)-3- Step (i): 1.2 (d, J = 6.7 Hz, 3H), 1.39 (d, J =7.0 Hz, 3H), 1.89 (h, J = 6.7 Hz, [M + H]⁺ (ES⁺), at 2.09 min, UVmethylbutanamido)ethyl) equivalents of 1H), 3.44 (d, J = 6.2 Hz, 1H),4.21 (d, J = 11.3 Hz, 1H), 4.42 (d, active. benzoic acid NaH and 2 J =11.3 Hz, 1H), 5.01 (p, J = 7.2 Hz, 1H), 6.67-6.80 (m, 2H), equivalentsof 7.08-7.18 (m, 2H), 7.40-7.50 (m, 2H), 7.84-7.93 (m, 2H), Intermediate8.33 (d, J = 8.2 Hz, 1H), 9.42 (s, 1H), 12.88 (s, 1H). 38 used, thenRoute L 42 (R)-N-((S)-1-(4-(1H- Route H 4, 24 ¹H NMR (400 MHz, DMSO) δ0.81 (d, J = 6.7 Hz, 3H), 0.87 (d, J = (LC/MS Method E): m/z 398tetrazol-5-yl)phenyl)ethyl)- 6.7 Hz, 3H), 1.42 (d, J = 7.1 Hz, 3H),1.88-2.00 (m, 1H), 3.51 [M + H]⁺ (ES⁺), at 1.99 min, UV2-((4-fluorobenzyl)oxy)-3- (d, J = 6.2 Hz, 1H), 4.35 (d, J = 11.8 Hz,1H), 4.54 (d, J = 11.8 active. methylbutanamide Hz, 1H), 4.99-5.10 (m,1H), 7.13-7.23 (m, 2H), 7.37-7.43 (m, 2H), 7.51-7.56 (m, 2H), 7.96-8.00(m, 2H), 8.39 (d, J = 8.2 Hz, 1H). Tetrazole N-H not observed. 43(R)-N-((S)-1-(4-(1H- Route H 4, 31 ¹H NMR (400 MHz, DMSO) δ 0.80-0.97(m, 6H), 1.38-1.49 (LC/MS Method E): m/z 448tetrazol-5-yl)phenyl)ethyl)- (m, 3H), 1.94-2.03 (m, 1H), 3.49-3.61 (m,1H), 4.47 (d, J = [M + H]⁺ (ES⁺), at 2.17 min, UV 3-methyl-2-((4- 12.0Hz, 1H), 4.66 (d, J = 12.0 Hz, 1H), 5.02-5.12 (m, 1H), active.(trifluoromethyl)benzyl)oxy) 7.53-7.63 (m, 4H), 7.69-7.78 (m, 2H),7.96-8.04 (m, 2H), butanamide 8.43-8.50 (m, 1H). Tetrazole N-H notobserved. 44 4-((S)-1-((R)-2-((3- Route E 1, 32 ¹H NMR (400 MHz, DMSO) δ0.82 (d, J = 6.7 Hz, 3H), 0.89 (d, J = (LC/MS Method D): m/z 448(ethylsulfonyl)benzyl)oxy)- Step (i): 1.2 6.7 Hz, 3H), 1.10 (t, J = 7.3Hz, 3H), 1.40 (d, J = 7.1 Hz, 3H), [M + H]⁺ (ES⁺), at 2.11 min, UV 3-equivalents of 1.91-2.02 (m, 1H), 3.29 (q, J = 7.3 Hz, 2H), 3.55 (d, J =6.3 Hz, active. methylbutanamido)ethyl) NaH used 1H), 4.47 (d, J = 12.6Hz, 1H), 4.67 (d, J = 12.6 Hz, 1H), 4.98- benzoic acid 5.11 (m, 1H),7.40-7.48 (m, 2H), 7.64-7.69 (m, 1H), 7.70- 7.75 (m, 1H), 7.79-7.85 (m,1H), 7.86-7.92 (m, 3H), 8.49 (d, J = 8.1 Hz, 1H), 12.90 (br.s, 1H). 454-((S)-1-((R)-2-((3- Route I 1 ¹H NMR (400 MHz, DMSO) δ 0.78 (d, J = 6.7Hz, 3H), 0.84 (d, J = (LC/MS Method D): m/z 386 (hydroxymethyl)benzyl)6.7 Hz, 3H), 1.38 (d, J = 7.1 Hz, 3H), 1.82-2.00 (m, 1H), 3.48 [M + H]⁺(ES⁺), at 1.68 min, UV oxy)-3- (d, J = 6.1 Hz, 1H), 4.30 (d, J = 11.8Hz, 1H), 4.40-4.58 (m, active. methylbutanamido)ethyl) 3H), 4.96-5.08(m, 1H), 5.13-5.24 (m, 1H), 7.14-7.33 (m, benzoic acid 4H), 7.39-7.48(m, 2H), 7.81-7.93 (m, 2H), 8.36 (d, J = 8.1 Hz, 1H), 12.83 (br.s, 1H).46 4-((1S)-1-((2R)-2-(1-(4- Route E 1, 34 ¹H NMR (400 MHz, DMSO-d₆) [NBmixture of diastereoisomers] (LC/MS Method H): m/z 388fluorophenyl)ethoxy)-3- Step (i): 1.2 δ 0.62-0.91 (m, 6H), 1.20-1.46 (m,6H), 1.77-2.00 (m, 1H), [M + H]⁺ (ES⁺), at 9.56 min, UVmethylbutanamido)ethyl) equivalents of 3.18 (d, J = 6.8 Hz, 0.5H), 3.52(d, J = 5.9 Hz, 0.6H), 4.31 (q, J = active. benzoic acid, mixture of NaHused 6.3 Hz, 0.4H), 4.45 (q, J = 6.4 Hz, 0.6H), 4.83 (p, J = 7.2 Hz,diastereomers 0.6H), 5.05 (p, J = 7.3 Hz, 0.4H), 7.08-7.24 (m, 2H),7.29- 7.36 (m, 2H), 7.40-7.48 (m, 2H), 7.81-7.87 (m, 1.2H), 7.89- 7.94(m, 0.8H), 7.97 (d, J = 8.2 Hz, 0.6H), 8.32 (d, J = 8.2 Hz, 0.4H), 12.90(s, 1H). 47 4-((1S)-1-(3-methyl-2-((4- Route J 3, 35 ¹H NMR (400 MHz,Methanol-d₄) [NB mixture of (LC/MS Method D): m/z 412 (oxetan-3-diastereoisomers] δ 0.85-1.00 (m, 6H), 1.44-1.51 (m, 3H), [M + H]⁺(ES⁺), at 2.23 & 2.26 yl)benzyl)oxy)butanamido) 1.93-2.08 (m, 1H),3.53-3.59 (m, 1H), 4.22-4.33 (m, 1H), min, UV active. ethyl)benzoicacid, mixture 4.42 (d, J = 11.7 Hz, 1H), 4.54 (d, J = 11.8 Hz, 0.5H),4.61 (d, J = of diastereomers 11.8 Hz, 0.5H), 4.70-4.77 (m, 2H),5.05-5.20 (m, 3H), 7.29- 7.48 (m, 6H), 7.93-8.02 (m, 2H), 8.37 (d, J =8.2 Hz, 0.4H), 8.44 (d, J = 8.1 Hz, 0.4H). 48 4-((1S)-1-(3-methyl-2-((3-Route K 3, 36 1H NMR (400 MHz, DMSO-d6) δ 0.83 (d, J = 6.8 Hz, 3H), 0.89(LC/MS Method D): m/z 412 (oxetan-3- (d, J = 6.7 Hz, 3H), 1.39 (d, J =7.0 Hz, 3H), 1.95 (h, J = 6.7 Hz, [M + H]⁺ (ES⁺), at 2.03 min, UVyl)benzyl)oxy)butanamido) 1H), 3.51 (d, J = 6.3 Hz, 1H), 4.22 (p, J =8.1 Hz, 1H), 4.33 (d, J = active. ethyl)benzoic acid, 11.9 Hz, 1H), 4.52(d, J = 11.9 Hz, 1H), 4.56-4.64 (m, 2H), diastereomer 1 4.93 (dd, J =8.4, 5.8 Hz, 2H), 5.07 (p, J = 7.2 Hz, 1H), 7.19- 7.26 (m, 1H),7.30-7.38 (m, 3H), 7.42 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.2 Hz, 2H),8.39 (d, J = 8.2 Hz, 1H). 49 4-((1S)-1-(3-methyl-2-((3- Route K 3, 36 1HNMR (400 MHz, DMSO-d6) δ 0.80 (d, J = 6.8 Hz, 3H), 0.87 (LC/MS MethodD): m/z412 (oxetan-3- (d, J = 6.7 Hz, 3H), 1.38 (d, J = 7.1 Hz, 3H),1.94 (h, J = 6.7 Hz, [M + H]⁺ (ES⁺), at 2.00 min, UVyl)benzyl)oxy)butanamido) 1H), 3.50 (d, J = 6.3 Hz, 1H), 4.19-4.29 (m,1H), 4.35 (d, J = active. ethyl)benzoic acid, 12.0 Hz, 1H), 4.52-4.65(m, 3H), 4.94 (ddd, J = 7.9, 5.9, 1.6 diastereomer 2 Hz, 2H), 5.02 (p, J= 7.2 Hz, 1H), 7.22-7.27 (m, 1H), 7.31- 7.40 (m, 3H), 7.44 (d, J = 8.1Hz, 2H), 7.88 (d, J = 8.1 Hz, 2H), 8.41 (d, J = 8.2 Hz, 1H), 12.93 (s,1H). 50 (R)-4-(1-(2-((3- Route C 5, 8 1H NMR: (400 MHz, DMSO-d6) δ 0.88(dd, 6H, J = 6.8 Hz & (LC/MS Method D): m/z 402 chlorobenzyl)oxy)-3- J=14.8 Hz), 1.35-1.14 (m, 4H), 2.00-1.93 (m, 1H), 3.51 (d, 1H, [M +H]⁺(ES+), at 2.36 min, UV methylbutanamido) J = 6.0 Hz), 4.43 (d, 1H, J= 12.4 Hz), 4.59 (d, 1H, J = 12.4 Hz), 7.23 active. cyclopropyl)benzoicacid (d, 2H, J = 8.4 Hz), 7.41-7.34 (m, 3H), 7.473 (s, 1H), 7.83 (d, 2H,J = 8.8 Hz), 8.78 (s, 1H), 12.82 (s, 1H). 51 4-((1S)-1-((2R)-3-methyl-2-Route M 1, 39 1H NMR: (400 MHz, DMSO-d6): [NB mixture of (LC/MS MethodH): m/z 438 (1-(4- diastereoisomers] δ 0.70-0.66 (m, 3H), 0.85 (d, 3H, J= 6.4 Hz), [M + H]⁺ (ES⁺), at 10.00 min, UV (trifluoromethyl)phenyl)1.39 (d, 3H, J = 6.8 Hz), 1.61 (d, 3H, J = 6.4 Hz), 1.98-1.89 (m,active. ethoxy)butanamido)ethyl) 1H), 3.70-3.66 (m, 1H), 5.05-4.95 (m,1H), 5.42 (dd, 1H, J = benzoic acid, mixture of 5.2 Hz & 4.4 Hz), 6.11(d, 1H, J = 6.8 Hz), 7.49 (d, 2H, J = 8.4 Hz), diastereomers 7.68 (d,2H, J = 8.4 Hz), 7.74 (d, 2H, J = 8.4 Hz), 7.96 (d, 2H, J = 8.0 Hz),8.19 (dd, 1H, J = 8.0 Hz & 2.0 Hz). 52 (R)-4-(1-(2-((3- Route A 5, 17 ¹HNMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.91-7.73 (m, (LC/MS Method C):m/z 434 (difluoromethoxy)benzyl) 2H), 7.48-7.38 (m, 1H), 7.29-7.09 (m,6H), 4.62 (d, J = 12.4 [M + H]⁺ (ES⁺), at 2.41 min, UV oxy)-3- Hz, 1H),4.42 (d, J = 12.4 Hz, 1H), 3.51 (d, J = 6.1 Hz, 1H), 2.05- activemethylbutanamido) 1.91 (m, 1H), 1.31-1.10 (m, 4H), 0.91 (d, J = 6.7 Hz,3H), cyclopropyl)benzoic acid 0.87 (d, J = 6.8 Hz, 3H). One exchangeableproton not observed 53 4-((S)-1-((R)-3-methyl-2- Route N Example 1 1HNMR (400 MHz, CDCI) δ 0.81 (d, J = 6.8 Hz, 3H), 0.90 (d, J = (LC/MSMethod A): m/z 501 ((4- 6.9 Hz, 3H), 1.41 (d, J = 7.0 Hz, 3H), 1.99-2.08(m, 1H), 3.24 [M + H]+, 2.69 min., UV active(trifluoromethyl)benzyl)oxy) (s, 3H), 3.68 (d, J = 4.4 Hz, 1H), 4.57 (d,J = 12.1 Hz, 1H), 4.64 butanamido)ethyl)-N- (d, J = 12.1 Hz, 1H), 5.09(p, J = 7.2 Hz, 1H), 6.80 (d, J = 8.0 Hz, (methylsulfonyl)benzamide 1H),7.30 (d, J = 8.0 Hz, 2H), 7.44-7.50 (m, 2H), 7.62-7.67 (m, 2H), 7.84 (d,J = 8.1 Hz, 2H). 54 (R)-4-(1-(2-((3- Route C 5, 15 ¹H NMR: (400 MHz,DMSO) 0.91-0.84 (m, 6H), 1.25-1.14 (m, (LC/MS Method D): m/z 393cyanobenzyl)oxy)-3- 2H), 1.32-1.27 (m, 2H), 2.03-1.94 (m, 1H), 3.53 (d,1H, [M + H]⁺ (ES⁺), at 2.01 min., UV methylbutanamido) J = 6.0 Hz), 4.48(d, 1H, J = 12.4 Hz), 4.63 (d, 1H, J = 12.4 Hz), 7.23 active.cyclopropyl)benzoic acid (d, 2H, J = 8.4 Hz), 7.59 (t, 1H, J = 7.8 Hz),7.74 (d, 1H, J = 8.0 Hz), 7.84-7.784 (m, 3H), 7.88 (s, 1H), 8.80 (s,1H), 12.84 (s, 1H). 55 (R)-4-(1-(2-((2,2- Route C 5, 21 ¹H NMR (400 MHz,DMSO) 0.90-0.86 (m, 6H), 1.28-1.17 (m, 4H) (LC/MS Method D): m/z 448difluorobenzo[d][1,3]dioxol- 2.02-1.92 (m, 1H), 3.53 (d, 1H, J =5.6 Hz),4.5 (d, 1H, J =12.4 Hz), [M + H]⁺ (ES⁺), at2.13min., UV 5-yl)methoxy)-3-4.58 (d, 1H, J =12.0 Hz), 7.26-7.20 (m, 3H), 7.42 (d, 1H), 7.48 (s,active methylbutanamido) 1H), 7.83 (d, 2H, J = 8.4 Hz), 8.73 (s, 1H),12.81 (s, 1H). cyclopropyl)benzoic acid 56 (R)-4-(1-(2-((3- Route C 5,32 ¹H NMR: (400 MHz, DMSO) 0.92-0.85 (m, 6H), 1.08 (t, 3H, (LC/MS MethodH): m/z 477 (ethylsulfonyl)benzyl)oxy)- J = 7.4 Hz), 1.27-1.15 (m, 4H),2.01-1.96 (m, 1H), 3.31-3.26 (m, [M+18]⁺ (ES⁺), at 8.23 min., UV 3- 2H),3.53 (d, 1H, J = 6.0 Hz), 4.51 (d, 1H, J = 12.4 Hz), 4.72 (d, 1H, activemethylbutanamido) J = 12.4 Hz), 7.23 (d, 2H, J = 8.4 Hz), 7.67 (t, 1H, J= 7.6 Hz), 7.77 (d, cyclopropyl)benzoic acid 1H, J = 7.6 Hz), 7.83 (d,3H, J = 8.0 Hz), 7.90 (s, 1H), 8.83 (s, 1H), 12.86 (s, 1H). 57(R)-4-(1-(2-((3- Route C 5, 25 ¹H NMR: (400 MHz, DMSO) 0.98 (dd, 6H, J =6.4 Hz & J = 24.8 Hz), (LC/MS Method D): m/z 452 (difluoromethoxy)-4-1.24-1.16 (m, 3H), 1.31-1.26 (m, 2H), 1.99-1.95 (m, 1H), 3.51 (d, [M +H]⁺ (ES⁺), at 2.37 min., UV fluorobenzyl)oxy)-3- 1H, J = 6.4 Hz), 4.39(d, 1H, J = 12.0 Hz), 4.58 (d, 1H, J = 12.0 Hz), activemethylbutanamido) 7.28-7.20 (m, 2H), 7.34-7.30 (m, 1H), 7.44-7.39 (m,2H), 7.83 (d, cyclopropyl)benzoic acid 2H, J = 8.4 Hz), 8.78 (s, 1H),12.85 (s, 1H). 58 (R)-4-(1-(3-methyl-2-((3- Route A 5, 13 ¹H NMR: (400MHz, DMSO) 8.76 (s, 1H), 7.81 (d, 2H), 7.52(t 1H), (LC/MS Method C): m/z452 (trifluoromethoxy)benzyl)ox 7.44-7.38 (m, 2H), 7.34-7.28 (m, 1H),7.19 (d, 2H), 4.65 (d, 1H), [M + H]⁺ (ES⁺), at 2.72 min, UVy)butanamido)cyclopropyl) 4.46 (d, 1H), 3.53 (d. 1H), 2.05-1.93, (m,1H), 1.32-1.13 (m, 4H), active benzoic acid 0.89 (dd, 6H) 59(R)-4-((3-methyl-2-((4- Route A (Step 31, 40 1H NMR (400 MHz, DMSO-d6) δ0.86-0.92 (m, 6H), 1.95- (LC/MS Method B): m/z 410(trifluoromethyl)benzyl)oxy) (i)); then, 2.05 (m, 1H), 3.61 (d, J = 5.6Hz, 1H), 4.38 (d, J = 6.1 Hz, 2H), [M + H]+, 0.80 min., UV activebutanamido)methyl)benzoic Route C (Step 4.48 (d, J = 12.7 Hz, 1H), 4.69(d, J = 12.7 Hz, 1H), 7.35-7.40 acid 00) (m, 2H), 7.57-7.62 (m, 2H),7.70-7.74 (m, 2H), 7.86-7.91 (m, 2H), 8.57 (t, J = 6.2 Hz, 1H), 12.86(s, 1H). 60 (R)-4-(1-(2-((3- Route C 5, 30 ¹H NMR: (400 MHz, DMSO) 0.88(dd, 6H, J = 6.4 Hz & J = 19.6 Hz), (LC/MS Method D): m/z 412(methoxymethyl)benzyl) 1.13-1.07 (m, 4H), 2.00-1.92 (m, 1H), 3.29 (s,3H), 3.48 (d, 1H, [M + H]⁺ (ES⁺), at 2.14 min UV oxy)-3- J = 6.4 Hz),4.41-4.38 (m, 3H), 4.59 (d, 1H, J = 12.0 Hz), 7.26-7.23 active.methylbutanamido) (m, 3H), 7.37-7.29 (m, 3H), 7.83 (d, 2H, J = 8.4 Hz),8.76 (s, 1H), cyclopropyl)benzoic acid 12.83 (s, 1H 61 (R)-4-(1-(2-((4-Route C 5, 22 ¹H NMR: (400 MHz, DMSO) δ: 0.92 (dd, 6H, J = 5.6 Hz &(LC/MS Method D): m/z 436 (difluoromethyl)-3- J = 14.8 Hz), 1.30-1.20(m, 4H), 2.05-1.95 (m, 1H), 3.55 (d, 1H, [M + H]⁺ (ES⁺), at 2.01 min. UVfluorobenzyl)oxy)-3- J = 4.4 Hz), 4.50 (d, 1H, J = 12.4 Hz), 4.67 (d,1H, J = 12.8 Hz), 7.22 active. methylbutanamidojcyclopr (t, 1H, J = 56Hz), 7.25 (d, 2H, J = 7.2 Hz), 7.44-7.36 (m, 2H), 7.65 opyl)benzoic acid(t, 1H, J = 7.6 Hz), 7.84 (d, 2H, J = 6.8 Hz), 8.82 (s, 1H), 12.84 (s,1H). 62 (R)-4-(1-(2-((4- Route C 5, 49 ¹H NMR: (400 MHz, DMSO) 0.88 (dd,6H, J = 6.8 Hz & J = 17.6 Hz), (LC/MS Method D): m/z 418(difluoromethyl)benzyl) 1.30-1.15 (m, 4H), 2.00-1.95 (m, 1H), 3.52-3.51(d, 1H, [M + H]⁺ (ES⁺), at 2.21 min. UV oxy)-3- J = 6.0 Hz), 4.45 (d,1H, J = 12.4 Hz), 4.65 (d, 1H, J = 12.4 Hz), 7.04 active.methylbutanamido)cyclopr (t, 1H, J = 55.8 Hz), 7.24 (d, 2H, J = 8.4 Hz),7.59-7.52 (m, 4H), 7.83 opyl)benzoic acid (d, 2H, J = 8.4 Hz), 8.77 (s,1H), 12.80 (s, 1H). 63 (R)-4-(1-(3-methyl-2-((4- Route N Example 2 ¹HNMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H),8.80 (s, 1H), (LC/MS Method C):m/z 513 (trifluoromethyl)benzyl)oxy) 7.88-7.83 (m, 2H), 7.78-7.73 (m,2H), 7.65-7.60 (m, 2H), 7.29- [M + H]⁺ (ES⁺), at 2.79 min. UVbutanamido)cyclopropyl)- 7.24 (m, 2H), 4.69 (d, J = 12.7 Hz, 2H), 4.51(d, J = 12.7 Hz, 1H), active. N- 3.55 (d, J = 6.1 Hz, 1H), 2.01 (dt, J=13.3, 6.7 Hz 1H), 1.36-1.17 (methylsulfonyl)benzamide (m, 4H), 0.93 (d,J = 6.8 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H). 64 (R)-4-(2-(3-methyl-2-((4-Route A (Step 31, 41 1H NMR (400 MHz, DMSO-d6) δ 0.88 (d, J = 6.8 Hz,3H), 0.91 (LC/MS Method C): m/z 438 (trifluoromethyl)benzyl)oxy) (i));then, (d, J = 6.7 Hz, 3H), 1.57 (d, J = 9.7 Hz, 6H), 1.97 (h, J = 6.7Hz, [M + H]⁺ (ES⁺), 2.65 min. UV butanamido)propan-2- Route C (Step 1H),3.54 (d, J = 6.4 Hz, 1H), 4.50 (d, J = 12.7 Hz, 1H), 4.63 (d, activeyl)benzoic acid 00) J = 12.7 Hz, 1H), 7.39-7.45 (m, 2H), 7.58-7.63 (m,2H), 7.72- 7.77 (m, 2H), 7.82-7.87 (m, 2H), 8.04 (s, 1H), 12.74 (s, 1H).65 (R)-4-(1-(2-((3- Route C 5, 29 ¹H NMR: (400 MHz, DMSO) 0.67-0.64 (m,2H), 0.92-0.84 (m, (LC/MS Method D): m/z 408 cyclopropylbenzyl)oxy)-3-6H), 0.95-0.93 (m, 2H), 1.23-1.17 (m, 2H), 1.28-1.25 (m, 2H), [M + H]⁺(ES⁺), at2.35min. UV methylbutanamido) 1.98-1.87 (m, 2H), 3.47 (d, 1H, J= 6.4 Hz), 4.37 (d, 1H, active. cyclopropyl)benzoic acid J = 12.0 Hz),4.54 (d, 1H, J = 12.0 Hz), 7.01 (d, 1H), 7.06 (s, 1H), 7.14 (d, 1H, J =7.6 Hz), 7.25-7.21 (m, 3H), 7.83 (d, 2H, J = 8.4 Hz), 8.72 (s, 1H),12.84 (s, 1H). 66 4-((S)-1-((R)-2- Route C 1, 42 1H NMR (400 MHz,Methanol-d4) δ 0.93 (d, J = 6.9 Hz, 3H), (LC/MS Method D): m/z 396(imidazo[1,2-a]pyridin-7- Step (i): 3 0.98 (d, J = 6.7 Hz, 3H), 1.48 (d,J = 7.0 Hz, 3H), 1.97-2.10 (m, [M + H]⁺ (ES⁺), at 1.68 min, UVyl)methoxy)-3- equivalents of 1H), 3.61 (d, J = 6.3 Hz, 1H), 4.50 (d, J= 12.9 Hz, 1H), 4.67 (d, active. methylbutanamido)ethyl) NaH used J =12.8 Hz, 1H), 5.06-5.16 (m, 1H), 6.95-7.00 (m, 1H), 7.42 benzoic acid(d, J = 8.1 Hz, 2H), 7.55-7.62 (m, 2H), 7.85 (s, 1H), 7.95 (d, J = 8.1Hz, 2H), 8.43 (d, J = 7.0 Hz, 1H), 8.58 (d, J = 8.1 Hz, 1H). 67(R)-4-(1-(2-((2- Route C 5, 44 ¹H NMR: (400 MHz, DMSO) 0.99-0.85 (m,6H), 1.21-1.15 (m, (LC/MS Method D): m/z 435 (difluoromethoxy)pyridin-4-2H), 1.32-1.23 (m, 2H), 2.04-1.99 (m, 1H), 3.56 (d, 1H, [M + H]⁺ (ES⁺),at 2.00 min. UV yl)methoxy)-3- J = 6.0 Hz), 4.50 (d, 1H, J = 14.0 Hz),4.67 (d, 1H, J = 10.0 Hz), 7.11 active. methylbutanamido) (s, 1H), 7.23(d, 2H, J = 8.4 Hz), 7.28 (d, 1H, J = 5.2 Hz), 7.72 (t, 1H,cyclopropyl)benzoic acid J = 73.2 Hz), 7.83 (d, 2H, J = 8.4 Hz), 8.23(d, 1H, J = 4.8 Hz), 8.82 (s, 1H), 12.83 (s, 1H). 68 (R)-4-(1-(2-((4-Route C 5, 45 ¹H NMR: (400 MHz, DMSO-d6) δ: 0.91 (t, 6H, J = 7.2 Hz),1.31- (LC/MS Method D): m/z 435 (difluoromethoxy)pyridin-2- 1.15 (m,4H), 2.06-2.01 (m, 1H), 3.64 (d, 1H, J = 6. 0Hz) 4.54 (d, [M + H]⁺(ES⁺), atl.99min. UV yl)methoxy)-3- 1H, J = 13.6 Hz), 4.68 (d, 1H, J =13.2 Hz), 7.15 (dd, 1H, J = 2.4 Hz & active. methylbutanamido) J = 5.6Hz), 7.32-7.24 (m, 3H), 7.51 (t, 1H, J = 72.4 Hz), 7.81 (d, 2H,cyclopropyl)benzoic acid J = 8.8 Hz), 8.54 (d, 1H, J = 5.6 Hz), 8.94 (s,1H), 12.82 (s, 1H) 69 (R)-N-(1-(4-(1H-tetrazol-5- Route H 50, 31 ¹H NMR:(400 MHz, DMSO) 0.90 (dd, 6H, J = 17.2 Hz & J = 6.8 Hz), (LC/MS MethodD): m/z 460 yl)phenyl)cyclopropyl)-3- 1.30-1.18 (m, 4H), 2.02-1.98 (m,1H), 3.54 (d, 1H, J = 6.0 Hz), [M + H]⁺ (ES⁺), at 2.05 min. UVmethyl-2-((4- 4.51 (d, 1H, J = 12.4 Hz), 4.70 (d, 1H J = 12.8 Hz), 7.36(d, 2H, active. (trifluoromethyl)benzyl)oxy) J = 8.4 Hz), 7.62 (d, 2H, J= 8.0 Hz), 7.75 (d, 2H, J = 8.0 Hz), 7.93 (d, butanamide 2H, J = 8.4Hz), 8.82 (s, 1H), 16.74 (s, 1H). 70 (R)-N-(1-(4-(1H-tetrazol-5- Route H50, 24 ¹H NMR: (400 MHz, DMSO) 0.87 (dd, 6H, J = 6.8 Hz & J = 16.8 Hz),(LC/MS Method D): m/z 410 yl)phenyl)cyclopropyl)-2- 1.15-1.09 (m, 2H),1.23-1.18 (m, 2H), 1.98-1.93 (m, 1H), 3.48- [M + H]⁺ (ES⁺), at 2.50 min.UV ((4-fluorobenzyl)oxy)-3- 3.39 (m, 1H), 4.38 (d, 1H, J = 11.2 Hz),4.57 (d, 1H, J = 11.6 Hz), active. methylbutanamide 7.22-7.17 (m, 4H),7.44-7.41 (m, 2H), 7.85 (d, 2H, J = 8.4 Hz), 8.69 (s, 1H). 71(R)-N-(1-(4-(1H-tetrazol-5- Route H 50, 20 ¹H NMR: (400 MHz, DMSO) δ:0.91-0.86 (m, 6H), 1.31-1.19 (m, (LC/MS Method D): m/z 428yl)phenyl)cyclopropyl)-2- 4H), 1.99-1.96 (m, 1H), 3.53 (d, 1H, J = 6.0Hz), 4.42 (d, 1H, [M + H]⁺ (ES⁺), at 2.21 min. UV((3,4-difluorobenzyl)oxy)-3- J = 12.0 Hz), 4.57 (d, 1H, J = 12.0 Hz),7.26-7.25 (m, 1H), 7.35 (d, active. methylbutanamide 2H, J = 8.4 Hz),7.51-7.41 (m, 2H), 7.95 (d, 2H, J = 8.4 Hz), 8.80 (s, 1H), 16.84 (s,1H). 72 (R)-N-(1-(4-(1H-tetrazol-5- Step 1 as 50, 17 ¹H NMR: (400 MHz,DMSO) 0.90 (dd, 6H, J = 6.8 Hz, J = 16.0 Hz), (LC/MS Method D): m/z 458yl)phenyl)cyclopropyl)-2- Route A, Step 1.23-1.17 (m, 2H), 1.31-1.26 (m,2H), 2.01-1.97 (m, 1H), 3.52 (d, [M + H]⁺ (ES⁺), at 2.01 min UV ((3- 2as Route Y 1H, J = 6.4 Hz), 4.43 (d, 1H, J = 12.4 Hz), 4.62 (d, 1H, J =12.0 Hz), active. (difluoromethoxy)benzyl)ox 7.13 (d, 1H, J = 8.4 Hz),7.26 (t, 1H, J = 76.6 Hz) 7.27-7.22 (m, 2H), y)-3-methylbutanamide 7.35(d, 2H, J = 8.4 Hz), 7.45-7.41 (m, 1H), 7.93 (d, 2H, J = 8.4 Hz), 8.80(s, 1H), 16.74 (s, 1H). 73 (R)-4-(1-(3-methyl-2-((4- Route O 31, 43 1HNMR (400 MHz, Methanol-d4) δ 0.87 (d, J = 6.9 Hz, 3H), (LC/MS Method A):m/z 450 (trifluoromethyl)benzyl)oxy) 0.94 (d, J = 6.7 Hz, 3H), 1.83-2.10(m, 3H), 2.49-2.70 (m, [M + H]⁺ (ES⁺), at 1.52 min, UVbutanamido)cyclobutyl) 4H), 3.47 (d, J = 6.3 Hz, 1H), 4.44-4.49 (m, 1H),4.63 (d, J = active. benzoic acid 12.4 Hz, 1H), 7.51-7.59 (m, 4H),7.62-7.68 (m, 2H), 7.82- 7.87 (m, 2H). 74 4-((S)-1-((R)-2-((2- Route EStep 1, 44 1H NMR (400 MHz, DMSO-d6) δ 0.85 (d, J = 6.8 Hz, 3H), 0.90(LC/MS Method D): m/z 423 (difluoromethoxy)pyridin-4- (i): 1-2 (d, J =6.7 Hz, 3H), 1.38 (d, J = 7.1 Hz, 3H), 1.98 (h, J = 6.7 Hz, [M + H]⁺(ES⁺), at 1.97 min, UV yl)methoxy)-3- equivalents of 1H), 3.56 (d, J =6.2 Hz, 1H), 4.44 (d, J = 14.0 Hz, 1H), 4.61 (d, active.methylbutanamido)ethyl) NaH used J = 14.0 Hz, 1H), 4.98-5.08 (m, 1H),7.06 (s, 1H), 7.24 (d, J = benzoic acid 5.0 Hz, 1H), 7.45 (d, J = 8.1Hz, 2H), 7.51-7.94 (m, 3H), 8.23 fd, J = 5.2 Hz, 1H), 8.49 (d, J = 8.2Hz, 1H), 12.89 (s, 1H). 75 (R)-4-(1-(3-methyl-2-((5- Route C 5, 18 ¹HNMR: (400 MHz, DMSO) 0.94-0.90 (m, 6H), 1.30-1.18 (m, (LC/MS Method D):m/z 437 (trifluoromethyl)pyridin-2- 4H), 2.07-2.02 (m, 1H), 3.67 (d, 1H,J = 6.0 Hz),4.63 (d, 1H), 4.77 [M + H]⁺ (ES⁺), at 2.00 min. UVyl)methoxy)butanamido) (d, 1H), 7.24 (d, 2H, J = 8.4 Hz), 7.77 (d, 1H, J= 8 Hz), 7.82 (d, 2H, active. cyclopropyl)benzoic acid J = 8.4 Hz), 8.27(d, 1H, J = 8 Hz), 8.91 (s, 1H), 8.94 (s, 1H), 12.93 (s, 1H). 76(R)-4-(1-(3-methyl-2-((6- Route C 5, 51 ¹H NMR: (400 MHz, DMSO) 0.90(dd, 6H, J = 6.8 Hz & J = 10.8 Hz), (LC/MS Method D): m/z 437(trifluoromethyl)pyridin-3- 1.21-1.15 (m, 2H), 1.32-1.24 (m, 2H),2.03-1.98 (m, 1H), 3.58 (d, [M + H]⁺ (ES⁺), at 1.97 min. UVyl)methoxy)butanamido) 1H, J = 5.6 Hz), 4.59 (d, 1H, J = 12.8 Hz), 4.74(d, 1H, J = 12.8 Hz), active. cyclopropyl)benzoic acid 7.23 (d, 2H, J =8 Hz), 7.83 (d, 2H, J = 8.4 Hz), 7.93 (d, 1H, J = 8 Hz), 8.11 (d, 1H, J= 8 Hz) 8.79 (s, 1H), 8.82 (s, 1H), 12.82 (s, 1H). 774-((S)-1-((R)-2-((4- Route E Step 1, 45 1H NMR (400 MHz, DMSO-d6) δ 0.86(d, J = 6.8 Hz, 6H), 1.39 (LC/MS Method D): m/z 423(difluoromethoxy)pyridin-2- (i): 1-2 (d, J = 7.0 Hz, 3H), 1.96-2.06 (m,1H), 3.66 (d, J = 5.7 Hz, 1H), [M + H]⁺ (ES⁺), at 1.71 min, UVyl)methoxy)-3- equivalents of 4.52 (d, J = 13.5 Hz, 1H), 4.62 (d, J =13.4 Hz, 1H), 5.04 (dq, J = active. methylbutanamido)ethyl) NaH and 27.2, 5.7 Hz, 1H), 7.15 (dd, J = 5.6, 2.5 Hz, 1H), 7.27 (d, J = 2.5benzoic acid equivalents of Hz, 1H), 7.29-7.69 (m, 3H), 7.85-7.93 (m,2H), 8.53 (d, J = Intermediate 5.7 Hz, 1H), 8.71 (d, J = 8.0 Hz, 1H),12.90 (s, 1H). 45 used 78 (R)-4-(1-(2-((3-chloro-4- Route C 5, 52 ¹HNMR: (400 MHz, DMSO) 0.90-0.86 (m, 6H), 1.28-1.18 (m, (LC/MS Method D):m/z 420 fluorobenzyl)oxy)-3- 4H), 2.00-1.95 (m, 1H), 3.51 (d, 1H, J =6.0 Hz), 4.42 (d, 1H, [M + H]⁺ (ES⁺), at 2.14 min. UV methylbutanamido)12.4 Hz), 4.56 (d, 1H, J = 12.4 Hz), 7.21 (d, 2H, J = 8.4 Hz), 7.42 (m,active. cyclopropyl)benzoic acid 2H), 7.63 (d, 1H, J = 7.6 Hz), 7.83 (d,2H, J = 8.4 Hz), 8.77 (s, 1H), 12.82 (s, 1H). 794-(1-((2R)-2-((4-chloro-5- Route C 5, 53 ¹H NMR: (400 MHz, DMSO) 0.98(q, 6H, J = 6.7 Hz), 1.27-1.18 (m, (LC/MS Method D): m/z 420fluorocyclohexa-1,3-dien-1- 4H), 2.08-1.94 (m, 1H), 3.52 (d, 1H, J = 6.0Hz), 4.44 (d, 1H, [M + H]⁺ (ES⁺), at2.17min. UV yl)methoxy)-3- J = 12.8Hz), 4.58 (d, 1H, J = 12.8 Hz), 7.28-7.20 (m, 3H), 7.47 (d, active.methylbutanamido) 1H, J = 6.4 Hz), 7.69 (t, 1H, J = 8.0 Hz), 7.83 (d,2H, J = 8.4 Hz), 8.78 cyclopropyl)benzoic acid (s, 1H), 12.83 (s, 1H 80(R)-2-((3- Route Y 50, 29 ¹H NMR: (400 MHz, DMSO) 0.63-0.68 (m, 2H),0.88 (dd, 6H, (LC/MS Method D): m/z 432 cyclopropylbenzyl)oxy)-N- j =6.8 Hz J = 17.2 Hz), 0.94 (dd, 2H j = 4 Hz J = 6 Hz), 1.15 (s, 2H), [M +H]⁺ (ES⁺), at 2.16 min. UV (1-(4-(2,3-dihydro-1H- 1.24-1.17 (m, 2H),1.97-1.89 (m, 2H), 3.46 (d, 2H J = 6.4 Hz), 4.35 active. tetrazol-5- (d,1H, J = 12 Hz), 4.55 (d, 1H, J = 12 Hz), 7.01 (d, 1H J = 7.6 Hz),yl)phenyl)cyclopropyl)-3- 7.07 (s, 1H), 7.26-7.12 (m, 4H), 7.85 (d, 2H J= 8 Hz), 8.61 (s, 1H). methylbutanamide 81 N-(cyclopropylsulfonyl)-4-Route N Example 5 1H NMR (400 MHz, DMSO-d6) δ 0.80 (d, J = 6.8 Hz, 3H),0.85 (LC/MS Method A): m/z 477 ((S)-1-((R)-2-((4- (d, J = 6.7 Hz, 3H),1.07-1.15 (m, 4H), 1.39 (d, J = 7.1 Hz, 3H), [M + H]⁺ (ES⁺), at 1.86min, UV fluorobenzyl)oxy)-3- 1.88-1.98 (m, 1H), 3.11 (tt, J =7.9, 4.9Hz, 1H), 3.50 (d, J = active. methylbutanamido)ethyl) 6.3 Hz, 1H), 4.33(d, J = 11.8 Hz, 1H), 4.52 (d, J = 11.8 Hz, 1H), benzamide 4.98-5.07 (m,1H), 7.15- 7.23 (m, 2H), 7.36-7.42 (m, 2H), 7.44-7.50 (m, 2H), 7.86-7.91 (m, 2H), 8.39 (d, J = 8.2 Hz, 1H), 12.01 (s, 1H). 82(R)-N-((S)-1-(4-(1H- Route H Step 4, 17 1H NMR (400 MHz, DMSO-d6) δ 0.83(d, J = 6.8 Hz, 3H), 0.88 (LC/MS Method D): m/z 446tetrazol-5-yl)phenyl)ethyl)- (i): 1-2 (d, J = 6.7 Hz, 3H), 1.41 (d, J =7.0 Hz, 3H), 1.90-2.01 (m, 1H), [M + H]⁺ (ES⁺), at 2.09 min, UV 2-((3-equivalents of 3.53 (d, J = 6.2 Hz, 1H), 4.37 (d, J = 12.4 Hz, 1H), 4.58(d, J = active. (difluoromethoxy)benzyl) NaH and 2 12.4 Hz, 1H),4.99-5.09 (m, 1H), 7.08-7.14 (m, 1H), 7.15- oxy)-3-methylbutanamideequivalents of 7.26 (m, 3H), 7.38-7.45 (m, 1H), 7.50 (d, J = 8.1 Hz,2H), 7.93- Intermediate 7.99 (m, 2H), 8.41 (d, J = 8.2 Hz, 1H). 17 used;Step (ii) 10 equivalents of NaN₃ and NH₄CI used 83 (R)-N-((S)-1-(4-(1H-Route H Step 4, 46 1H NMR (400 MHz, DMSO-d6) δ 0.61-0.68 (m, 2H), 0.82(d, J = (LC/MS Method D): m/z 420 tetrazol-5-yl)phenyl)ethyl)- (I): 1.26.8 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H), 0.90-0.97 (m, 2H), 1.40 [M + H]⁺(ES⁺), at 2.28 min, UV 2-((3- equivalents of (d, J = 7.0 Hz, 3H),1.85-1.99 (m, 2H), 3.49 (d, J = 6.2 Hz, 1H), active.cyclopropylbenzyl)oxy)-3- NaH used; 4.29 (d, J = 12.0 Hz, 1H), 4.52 (d,J = 12.0 Hz, 1H), 4.98-5.06 methylbutanamide Step (ii) 10 (m, 1H),6.97-7.06 (m, 2H), 7.10 (d, J = 7.5 Hz, 1H), 7.22 (t, J = equivalents of7.6 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.93 (d, J = 8.1 Hz, 2H), NaN₃and 8.28 (d, J = 8.2 Hz, 1H). NH4CI used 84 (R)-4-(1-(2-((6- Route C 5,54 ¹H NMR: (400 MHz, DMSO) 0.89 (dd, 6H, J = 6.8 Hz & J = 12.0 Hz),(LC/MS Method H): m/z 419 (difluoromethyl)pyridin-3- 1.28-1.09 (m, 4H),2.03-1.96 (m, 1H), 3.56 (d, 1H, J = 6.0 Hz), [M + H]⁺ (ES⁺), at 8.39min. UV yl)methoxy)-3- 4.53 (d, 1H, J = 12.8 Hz), 4.70 (d, 1H, J = 12.8Hz), 7.00 (t, 1H, active. methylbutanamido) J = 54.8 Hz), 7.24 (d, 2H, J= 8.4 Hz), 7.73 (d, 1H, J = 7.6 Hz), 7.83 (d, cyclopropyl)benzoic acid2H, J = 8.0 Hz), 8.02 (d, 1H, J = 7.2 Hz), 8.70 (s, 1H), 8.82 (d, 1H),12.86 (s, 1H). 85 4-((S)-1-((R)-2-((3- Route C Step 1, 47 1H NMR (400MHz, DMSO-d6) δ 0.65-0.74 (m, 2H), 0.78 (d, J = (LC/MS Method D): m/z414 cyclopropyl-4- (I): 1.3 6.7 Hz, 3H), 0.84 (d, J = 6.6 Hz, 3H),0.92-1.01 (m, 2H), 1.38 [M + H]⁺ (ES⁺), at 2.24 min, UVfluorobenzyl)oxy)-3- equivalents of (d, J = 7.0 Hz, 3H), 1.85-2.07 (m,2H), 3.45 (d, J = 6.2 Hz, 1H), active. methylbutanamido)ethyl)Intermediate 4.27 (d, J = 11.8 Hz, 1H), 4.46 (d, J = 11.9 Hz, 1H),4.96-5.06 benzoic acid 47 used; (m, 1H), 6.92 (d, J = 7.5 Hz, 1H),7.07-7.18 (m, 2H), 7.44 (d, J = 7.9 Hz, 2H), 7.88 (d, J = 8.1 Hz, 2H),8.38 (d, J = 8.1 Hz, 1H), 12.88 (s, 1H). 86 4-(1-(3-methyl-2-((3- RouteK 55, 36 1H NMR: (400 MHz, DMSO) 0.77-0.73 (m, 3H), 0.85-0.80 (m, (LC/MSMethod D): m/z 424 (oxetan-3- 5H), 0.92 (s, 2H), 1.25-1.22 (m, 2H),1.69-1.67 (m, 1H), 2.87 (d, [M + H]⁺ (ES⁺), at2.10min. UVyl)benzyl)oxy)butanamido) 1H, J = 7.2 Hz), 4.26-4.22 (m, 1H), 4.61-4.58(m, 2H), 4.85-4.78 active. cyclopropyl)benzoic acid, (m, 2H), 4.96-4.92(m, 2H), 7.15 (t, 1H, J = 3.4 Hz), 7.29 (s, 1H), enantiomer 1 7.41-7.35(m, 4H), 7.79 (d, 2H, J = 8.4 Hz), 12.83 (s, 1H). 874-(1-(3-methyl-2-((3- Route K 55, 36 1H NMR: (400 MHz, DMSO) 0.86-0.78(m, 7H), 0.93-0.90 (m, (LC/MS Method D): m/z 424 (oxetan-3- 2H),1.71-1.66 (m, 1H), 2.88 (d, 1H, J = 6.8 Hz), 4.28-4.22 (m, [M + H]⁺(ES⁺), at2.04min. UV yl)benzyl)oxy)butanamido) 1H), 4.61-4.57 (m, 2H),4.85-4.78 (m, 2H), 4.96-4.92 (m, 2H), active. cyclopropyl)benzoic acid,7.15 (t, 1H, J = 3.4 Hz), 7.29 (s, 1H), 7.41-7.35 (m, 4H), 7.80 (d,enantiomer 2 2H, J = 8.4 Hz), 12.83 (s, 1H). 88 (R)-4-(1-(2-((5- Route C5, 27 ¹H NMR: (400 MHz, DMSO) 0.93-0.89 (m, 6H), 1.28-1.18 (m, (LC/MSMethod D): m/z 419 (difluoromethyl)pyridin-2- 4H), 2.04-2.02 (m, 1H),3.65-3.64 (m, 1H), 4.75-4.57 (m, 2H), [M + H]⁺ (ES⁺), at 1.81 min. UVyl)methoxy)-3- 7.30-7.02 (m, 3H), 7.68 (d, 1H, J = 7.6 Hz), 7.82 (d, 2H,J = 7.2 Hz), active. methylbutanamido) 8.07-8.05 (m, 1H), 8.74 (s, 1H),8.93 (s, 1H). cyclopropyl)benzoic acid 89 (R)-4-(1-(2-((3-cyclopropyl-Route C 5, 47 ¹H NMR: (400 MHz, DMSO) 0.72-0.70 (m, 2H), 0.86 (dd, 6H,(LC/MS Method D): m/z 426 4-fluorobenzyl)oxy)-3- J = 6.8 Hz, J = 14.8Hz), 0.98-0.93 (m, 2H), 1.26-1.15 (m, 4H), 1.97- [M + H]⁺ (ES⁺), at 2.41min. UV methylbutanamido) 1.92 (m, 1H), 2.05-2.00 (m, 1H), 3.46 (d, 2H,J = 6.4 Hz), 4.33 (d, active. cyclopropyl)benzoic acid 1H, J = 12.0 Hz),4.50 (d, 1H, J = 11.6 Hz), 6.97 (d, 1H, J = 6.0 Hz), 7.20-7.09 (m, 4H),7.80 (d, 2H, J = 8.0 Hz), 8.66 (s, 1H). 90 4-((S)-1-((R)-2-((3- Route CStep 1,48 1H NMR (400 MHz, DMSO-d6) δ 0.83 (d, J = 6.8 Hz, 3H), 0.89(LC/MS Method D): m/z 460 (cyclopropylsulfonyl)benzyl) (ii): 3 (d, J =6.7 Hz, 3H), 1.00-1.16 (m, 4H), 1.39 (d, J = 7.1 Hz, 3H), [M + H]⁺(ES⁺), at 1.97 min, UV oxy)-3- equivalents of 1.91-2.02 (m, 1H),2.80-2.88 (m, 1H), 3.55 (d, J = 6.3 Hz, active. methylbutanamido)ethyl)LIOH•H2O 1H), 4.46 (d, J = 12.6 Hz, 1H), 4.67 (d, J = 12.5 Hz, 1H),4.99- benzoic acid used; 5.09 (m, 1H), 7.45 (d, J = 8.1 Hz, 2H),7.61-7.74 (m, 2H), 7.80- 7.85 (m, 1H), 7.85-7.93 (m, 3H), 8.48 (d, J =8.1 Hz, 1H). 91 (R)-4-(1-(2-((3- Route C 5, 48 ¹H NMR: (400 MHz, DMSO)0.90 (dd, 6H, J = 6.8 Hz & J = 18.4 Hz), (LC/MS Method D): m/z 472(cyclopropylsulfonyl)benzyl) 1.06-1.00 (m, 2H), 1.16-1.09 (m, 2H),1.25-1.20 (m, 2H), 1.32- [M + H]⁺ (ES⁺), at 2.14 min. UV oxy)-3- 1.25(m, 2H), 2.02-1.97 (m, 1H), 2.87-2.81 (m, 1H), 3.55 (d, 1H, active.methylbutanamido) J = 6.0 Hz), 4.52 (d, 1H, J = 12.4 Hz), 4.72 (d, 1H, J= 12.4 Hz), 7.24 cyclopropyl)benzoic acid (d, 2H, J = 8.4 Hz), 7.66 (t,1H, J = 7.6 Hz), 7.75 (d, 1H, J = 8.0 Hz), 7.84 (d, 3H, J = 8.4 Hz),7.91 (s, 1H), 8.82 (s, 1H), 12.84 (s, 1H) 92 4-((1S)-1-(2-cyclobutyl-2-Route P 59, 31, 60 ¹H NMR (400 MHz, DMSO-d6) [NB mixture ofdiastereoisomers] (LC/MS Method C): m/z 436 ((4- δ 8.38 (t, J = 7.7 Hz,1H), 7.91-7.81 (m, 2H), 7.77-7.67 (m, [M + H]⁺ (ES⁺), at 2.54 and 2.64(trifluoromethyl)benzyl)oxy) 2H), 7.62-7.52 (m, 2H), 7.42-7.32 (m, 2H),5.00 (h, J = 7.3 min, UV active. acetamido)ethyl)benzoic Hz, 1H), 4.63(dd, J = 12.8, 8.6 Hz, 1H), 4.45 (d, J = 12.7 Hz, acid, mixture of 1H),3.76 (d, J = 7.1 Hz, 1H), 2.65-2.53 (m, 1H), 2.00-1.66 diastereomers (m,6H), 1.37 (dd, J = 7.1, 1.1 Hz, 3H). One exchangeable proton notobserved. 93 4-((1S)-1-(2-cyclobutyl-2- Route P 59, 31, 60 ¹H NMR (400MHz, DMSO-d6) δ 8.43 (d, J = 8.2 Hz, 1H), 7.96- (LC/MS Method A): m/z436 ((4- 7.87 (m, 2H), 7.84-7.75 (m, 2H), 7.70-7.57 (m, 2H), 7.43- [M +H]⁺ (ES⁺), at 2.10 min, UV (trifluoromethyl)benzyl)oxy) 7.31 (m, 2H),5.14-5.01 (m, 1H), 4.68 (d, J = 12.7 Hz, 1H), 4.51 active.acetamido)ethyl)benzoic (d, J = 12.7 Hz, 1H), 3.82 (d, J = 7.2 Hz, 1H),2.72-2.60 (m, acid, diastereoisomer 1 1H), 2.03-1.76 (m, 6H), 1.44 (d, J= 7.0 Hz, 3H). One exchangeable proton not observed. 944-((1S)-1-(2-cyclobutyl-2- Route P 59, 31, 60 ¹H NMR (400 MHz, DMSO-d6)δ 8.39 (d, J = 8.2 Hz, 1H), 7.92- (LC/MS Method A): m/z 436 ((4- 7.83(m, 2H), 7.79-7.71 (m, 2H), 7.63-7.52 (m, 2H), 7.43- [M + H]⁺ (ES⁺), at2.02 min, UV (trifluoromethyl)benzyl)oxy) 7.26 (m, 2H), 5.10-4.91 (m,1H), 4.65 (d, J = 12.8 Hz, 1H), 4.46 active. acetamido)ethyl)benzoic (d,J = 12.8 Hz, 1H), 3.76 (d, J = 7.0 Hz, 1H), 2.66-2.56 (m, acid,diastereoisomer 2 1H), 1.99-1.70 (m, 6H), 1.38 (d, J = 7.1 Hz, 3H). Oneexchangeable proton not observed. 95 4-(1-(2-cyclobutyl-2-((3- Route Q58, 6 ¹H NMR (400 MHz, DMSO-d6) [NB mixture of enantiomers] δ (LC/MSMethod C): m/z 458 (methylsulfonyl)benzyl)oxy) 12.77 (br s, 1H), 8.77(s, 1H), 7.96-7.94 (m, 1H), 7.91-7.80 [M + H]⁺ (ES⁺), at 1.80 min, UVacetamido)cyclopropyl) (m, 3H), 7.79-7.74 (m, 1H), 7.71-7.64 (m, 1H),7.21-7.17 active. benzoic acid, mixture of (m, 2H), 4.71 (d, J = 12.6Hz, 1H), 4.54 (d, J = 12.6 Hz, 1H), enantiomers 3.75 (d, J = 7.1 Hz,1H), 3.21 (s, 3H), 2.70-2.61 (m, 1H), 2.04- 1.73 (m, 6H), 1.27- 1.16 (m,4H). 96 4-(1-(2-cyclobuty l-2-((4- Route Q 58, 31 ¹H NMR (400 MHz,DMSO-d6) [NB mixture of enantiomers] δ (LC/MS Method A): m/z 448(trifluoromethyl)benzyl)oxy) 8.71 (s, 1H), 7.84-7.70 (m, 4H), 7.65-7.53(m, 2H), 7.21- [M + H]⁺ (ES⁺), at 2.79 min, UV acetamido)cyclopropyl)7.03 (m, 2H), 4.68 (d, J = 12.7 Hz, 1H), 4.52 (d, J = 12.7 Hz, active.benzoic acid, mixture of 1H), 3.73 (d, J = 7.0 Hz, 1H), 2.73-2.59 (m,1H), 2.05-1.72 enantiomers (m, 5H), 1.34-1.10 (m, 5H). One exchangeableproton not observed. 97 4-(1-(2-cyclobutyl-2-((3,4- Route Q 58, 20 ¹HNMR (400 MHz, DMSO-d6) [NB mixture of enantiomers] δ (LC/MS Method C):m/z 416 difluorobenzyl)oxy)acetamido) 8.69 (s, 1H), 7.82-7.77 (m, 2H),7.53-7.40 (m, 2H), 7.28- [M + H]⁺ (ES⁺), at 2.34 min, UVcyclopropyl)benzoic 7.20 (m, 1H), 7.14-7.07 (m, 2H), 4.55 (d, J = 12.2Hz, 1H), 4.42 active. acid, mixture of (d, J = 12.2 Hz, 1H), 3.70 (d, J= 7.0 Hz, 1H), 2.67-2.58 (m, enantiomers 1H), 1.98-1.72 (m, 6H),1.29-1.21 (m, 2H), 1.18-1.11 (m, 2H). One exchangeable proton notobserved. 98 4-(1-(2-((3- Route Q 58, 8 ¹H NMR (400 MHz, DMSO-d₆) [NBmixture of enantiomers] δ (LC/MS Method C): m/z 414 chlorobenzyl)oxy)-2-8.71 (s, 1H), 7.84-7.77 (m, 2H), 7.49-7.46 (m, 1H), 7.42- [M + H]⁺(ES⁺), at 2.04 min, UV cyclobutylacetamido) 7.31 (m, 3H), 7.17-7.08 (m,2H), 4.58 (d, J = 12.4 Hz, 1H), 4.43 active. cyclopropyl)benzoic acid,(d, J = 12.4 Hz, 1H), 3.70 (d, J = 7.1 Hz, 1H), 2.70-2.58 (m, mixture ofenantiomers 1H), 2.03-1.70 (m, 5H), 1.31-1.18 (m, 3H), 1.17-1.08 (m,2H). One exchangeable proton not observed. 99 4-(1-(2-cyclobutyl-2-((3-Route R 58, 17 ¹H NMR (400 MHz, DMSO-d) [NB mixture of enantiomers] δ(LC/MS Method C): m/z 446 (difluoromethoxy)benzyl)oxy) 8.69 (br s, 1H),7.83-7.76 (m, 2H), 7.47-7.01 (m, 7H), 4.60 (d, [M + H]⁺ (ES⁺), at 2.41min, UV acetamido)cyclopropyl) J = 12.5 Hz, 1H), 4.42 (d, J = 12.4 Hz,1H), 3.70 (d, J = 7.1 Hz, active. benzoic acid, mixture of 1H),2.68-2.58 (m, 1H), 1.97-1.72 (m, 6H), 1.36-1.12 (m, enantiomers 4H). Oneexchangeable proton not observed. 100 (S)-4-(1-(2-cyclobutyl-2-((3-Route R 58, 17 ¹H NMR (400 MHz, DMSO-d6) δ 12.84 (br s, 1H), 8.71 (s,1H), (LC/MS Method C): m/z 446 (difluoromethoxy)benzyl) 7.87-7.74 (m,2H), 7.49-7.01 (m, 7H), 4.61 (d, J = 12.4 Hz, [M + H]⁺ (ES⁺), at 2.34min, UV oxy)acetamido)cyclopropyl) 1H), 4.43 (d, J = 12.4 Hz, 1H), 3.70(d, J = 7.1 Hz, 1H), 2.72- active. benzoic acid 2.57 (m, 1H), 2.03-1.68(m, 6H), 1.34-1.10 (m, 4H). 101 (R)-4-(1-(2-cyclobutyl-2- Route R, S 58,17 (Route R) ¹H NMR (400 MHz, DMSO-d) δ 12.87 (br s, 1H), 8.71 (s, 1H),(LC/MS Method C): m/z 446 ((3- (or T) 61, 62, 63, 17 7.87-7.77 (m, 2H),7.49-7.02 (m, 7H), 4.61 (d, J = 12.4 Hz, [M + H]⁺ (ES⁺), at 2.33 min, UV(difluoromethoxy)benzyl) (Route S) 1H), 4.43 (d, J = 12.4 Hz, 1H), 3.70(d, J = 7.0 Hz, 1H), 2.70- active. oxy)acetamido)cyclopropyl) 2.57 (m,1H), 2.04-1.68 (m, 6H), 1.33-1.10 (m, 4H). (LC/MS Method D): m/z 446benzoic acid [M + H]⁺ (ES⁺), at 2.00 min, UV active.

TABLE 3 Route & Intermediate intermediates Name Data 1 Route 1 methyl4-((S)-1-((R)-2-hydroxy-3- (LC/MS Method B): m/z 280 [M + H]⁺methylbutanamido)ethyl)benzoate (ES⁺), at 1.04 min, UV active. 2 Route 2methyl 4-((1S)-1-(2-hydroxy-3- (LC/MS Method D): m/z 280 [M + H]⁺methylbutanamido)ethyl)benzoate (ES⁺), at 1.69 min, UV active. 3 Route 2methyl 4-((1S)-1-(3-methyl-2- (LC/MS Method D): m/z 358 [M + H]⁺((methylsulfonyl)oxy)butanamido) (ES⁺), at 1.86 min, UV active.ethyl)benzoate 4 Route 3 (R)-N-((S)-1-(4-cyanophenyl) (LC/MS Method D):m/z 247 [M + H]⁺ ethyl)-2-hydroxy-3- (ES⁺), at 1.55 min, UV active.methylbutanamide 5 Route 4 methyl (R)-4-(1-(2-hydroxy-3- (LC/MS MethodB): m/z 292 [M + H]⁺ methylbutanamido)cyclopropyl) (ES⁺), at 1.06 min,UV active. benzoate 6 1-(bromomethyl)-3- Commercially available(methylsulfonyl) benzene CAS: 82657-76-9 7 1-(bromomethyl)-4-Commercially available (methylsulfonyl)benzene CAS: 53606-06-7 81-(bromomethyl)-3-chlorobenzene Commercially available CAS: 766-80-3 91-(bromomethyl)-3- Commercially available (difluoromethyl) benzene CAS:1263178-51-3 10 1-(bromomethyl)-3- Commercially available(trifluoromethyl) benzene CAS: 402-23-3 111-(bromomethyl)-3-fluorobenzene Commercially available CAS: 456-41-7 12Benzyl bromide Commercially available CAS: 100-39-0 131-(bromomethyl)-3- Commercially available (trifluoromethoxy)benzene CAS:159689-88-0 14 4-(bromomethyl)benzonitrile Commercially available CAS:17201-43-3 15 3-(bromomethyl)benzonitrile Commercially available CAS:28188-41-2 16 1-(bromomethyl)-4- Commercially available(difluoromethoxy)benzene CAS: 3447-53-8 17 1-(bromomethyl)-3-Commercially available (difluoromethoxy)benzene CAS: 72768-95-7 182-(bromomethyl)-5- Commercially available (trifluoromethyl) pyridineCAS: 1000773-62-5 19 4-(pentafluorosulfur)benzyl bromide Commerciallyavailable CAS: 1126969-29-6 20 4-(bromomethyl)-1,2- Commerciallyavailable difluorobenzene CAS: 85118-01-0 21 5-(bromomethyl)-2,2-Commercially available difluorobenzo[d][1,3]dioxole CAS: 68119-30-2 22Route 5 4-(bromomethyl)-1- ¹H NMR (400 MHz, DMSO) δ 4.73 (s,(difluoromethyl)-2-fluorobenzene 2H), 7.19 (t, J = 54 Hz, 1H), 7.38-7.51(m, 2H), 7.56-7.67 (m, 1H). 23 1-(bromomethyl)-4- Commercially availablecyclopropylbenzene CAS: 1150617-57-4 24 1-(bromomethyl)-4-fluorobenzeneCommercially available CAS: 459-46-1 25 Route 5, 4-(bromomethyl)-2- ¹HNMR (400 MHz, DMSO) δ 4.71 (s, Intermediate 26(difluoromethoxy)-l-fluorobenzene 2H), 7.03-7.52 (m, 4H). 263-(difluoromethoxy)-4- Commercially available fluorobenzaldehyde CAS:1214367-20-0 27 Route 6 2-(bromomethyl)-5- (LC/MS Method D): m/z 222[M + H]⁺ (difluoromethyl)pyridine (ES⁺), at 2.01 min, UV active. 284-(bromomethyl)-1-fluoro-2- Commercially available (methylsulfonyl)benzene CAS: 1192347-88-8 29 1-(bromomethyl)-3- Commercially availablecyclopropylbenzene CAS: 1260850-05-2 30 1-(bromomethyl)-3- Commerciallyavailable (methoxymethyl)benzene CAS: 125604-03-7 314-(trifluoromethyl)benzyl bromide Commercially available CAS: 402-49-332 Route 7 1-(bromomethyl)-3- 'H NMR (400 MHz, DMSO) δ1.10 (t, J =(ethylsulfonyl)benzene 7.4 Hz, 3H), 3.31 (q, J = 7.4 Hz, 2H), 4.84 (s,2H), 7.62-7.72 (m, 1H), 7.81-7.86 (m, 2H), 7.97-8.00 (m, 1H). 33 Route 8methyl 4-((S)-1-((R)-2-hydroxy-3- (LC/MS Method D): m/z 294 [M + H]⁺methylbutanamido)ethyl)-2- (ES⁺), at 3.03 min, UV active. methylbenzoate34 1-(1-Bromoethyl)-4-fluorobenzene Commercially available CAS:65130-46-3 35 [4-(oxetan-3-yl)phenyl]methanol Commercially availableCAS: 1781691-11-9 36 Route 9 (3-(oxetan-3-yl)phenyl)methanol 1H NMR (400MHz, DMSO-d6) δ 4.23 (p, J = 7.7 Hz, 1H), 4.50 (d, J = 5.5 Hz, 2H), 4.60(t, J = 6.3 Hz, 2H), 4.94 (dd, J = 8.4, 5.8 Hz, 2H), 5.21 (t, J = 5.7Hz, 1H), 7.17- 7.39 (m, 4H) 37 1-(Bromomethyl)-3-(2-propen-1-Commercially available yloxy)benzene CAS: 69411-94-5 381-(Bromomethyl)-4-(2-propen-1- Commercially available yloxy)benzene CAS:143116-30-7 39 1-(1-Bromoethyl)-4- Commercially available(trifluoromethyl)benzene CAS: 68120-42-3 40 Route 8 methyl4-[[[(2R)-2-hydroxy-3- 1H NMR (400 MHz, DMSO-d6) δ 0.76 (d,methyl-butanoyl]amino]methyl] J = 6.8 Hz, 3H), 0.90 (d, J = 6.9 Hz, 3H),benzoate 1.95-2.04 (m, 1H), 3.73 (dd, J = 5.6, 3.7 Hz, 1H), 3.84 (s,3H), 4.29-4.41 (m, 2H), 5.44 (d, J = 5.5 Hz, 1H), 7.37-7.43 (m, 2H),7.87-7.93 (m, 2H), 8.37 (t, J = 6.3 Hz, 1H). 41 methyl4-[1-[[(2R)-2-hydroxy-3- 1H NMR (400 MHz, DMSO-d6) δ 0.76 (d,methyl-butanoyl]amino]-1-methyl- J = 6.7 Hz, 3H), 0.87 (d, J = 6.9 Hz,3H), ethyl]benzoate 1.49- 1.67 (m, 6H), 1.87-2.02 (m, 1H), 3.58-3.67 (m,1H), 3.76-3.88 (m, 3H), 5.25-5.34 (m, 1H), 7.43-7.52 (m, 2H), 7.73 (s,1H), 7.82-7.91 (m, 2H). 42 Route 10 Imidazo[1,2-a]pyridine-7-methanol(LC/MS Method D): m/z 167 [M + H]⁺ (ES⁺), at 1.08 min, UV active. 43Route 8 (2R)-N-[1-(4- (LC/MS Method B): m/z 273 [M + H]⁺cyanophenyl)cyclobutyl]-2- (ES⁺), at 1.10 min, UV active.hydroxy-3-methyl-butanamide 44 4-(bromomethyl)-2- Commercially available(difluoromethoxy)pyridine CAS: 1268517-84-5 45 2-(Bromomethyl)-4-Commercially available (difluoromethoxy)pyridine CAS: 1375098-13-7 461-(bromomethyl)-3- Commercially available cyclopropylbenzene CAS:1260850-05-2 47 Route 6 4-(bromomethyl)-2-cyclopropyl-1- 1H NMR (400MHz, DMSO-d6) δ 0.67- fluorobenzene 0.76 (m, 2H), 0.94-1.04 (m, 2H),1.96- 2.09 (m, 1H), 4.65 (s, 2H), 7.05-7.17 (m, 2H), 7.22-7.29 (m, 1H).48 Route 11 1-(bromomethyl)-3- 1H NMR (400 MHz, DMSO-d6) δ 1.01-(cyclopropylsulfonyl)benzene 1.17 (m, 4H), 2.82-2.91 (m, 1H), 4.83 (s,2H), 7.62-8.03 (m, 4H). 49 1-(bromomethyi)-4- Commercially available(difluoromethyl)benzene CAS: 873373-34-3 50 Route 12 (R)-N-(1-(4- (LC/MSMethod D): m/z 259 [M + H]⁺ cyanophenyl)cyclopropyl)-2- (ES⁺),at1.40min. hydroxy-3-methylbutanamide 51 5-(Bromomethyl)-2- Commerciallyavailable (trifluoromethyl)pyridine CAS: 108274-33-5 523-Chioro-4-fluorobenzyl bromide Commercially available CAS: 192702-01-553 4-(Bromomethyl)-1-chloro-2- Commercially available fluorobenzene CAS:206362-80-3 54 Route 6 5-(bromomethyi)-2- (LC/MS Method D): m/z 222 [M +H]⁺ (difluoromethyl)pyridine (ES⁺), at 1.83 min. 55 Route 2 step(ii)methyl 4-(1-(3-methyl-2- (LC/MS Method D): m/z 370 [M + H]⁺ using((methylsulfonyl)oxy)butanamido) (ES⁺), at 1.79 min Intermediate 5cyclopropy)benzoate 56 1-(bromomethyl)-3- Commercially availablemethoxybenzene CAS: 874-98-6 57 Route 1 using methyl 4-((S)-1-((S)-2-hydroxy-3- LC/MS (Method C): m/z 438 [M + H]⁺, (2S)-2-hydroxy-methylbutanamido)ethyl)benzoate (ES⁺), at 1.71 min 3-methyl- butanoicacid 58 Route 13 using methyl 4-(1-(2-cyclobutyl-2- LC/MS (Method B):m/z 304 [M + H]+ Intermediate 62 hydroxyacetamido)cyclopropyl) (ES+), at1.09 min, UV active. benzoate 59 methyl 2-cyclobutyl-2- Commerciallyavailable hydroxyacetate CAS: 1517761-58-8 60 methyl(S)-4-(1-aminoethyl) Commercially available benzoate CAS: 222714-37-6 612-amino-2-cyclobutylacetic acid Commercially available CAS: 28024-69-362 methyl 4-(1-aminocyclopropyl) Commercially available benzoate CAS:1006037-03-1 63 (R)-2-methoxy-2-phenylacetic acid Commercially availableCAS: 3966-32-3

BIOLOGICAL ACTIVITY

Cloning, Baculovirus generation, large scale infection of HEK293 cellsand membrane preparation: Human prostaglandin E2 receptor 4 (EP4) wascloned into pBacMam expression vector (GeneScript, UK). Transposition ofEP4 DNA was performed using Invitrogen's Bac-to-Bac BaculovirusExpression Systems. P0 baculovirus was generated by transfecting SF9Cells with bacmid DNA using Cellfectin II transfection reagent(ThermoFisher Scientific, UK, catalog number 10362-100). Following P0generation P1 virus was then generated ready for large scale infectionand membrane preparation. HEK293 cells were grown in DMEM+Glutamax,supplemented with 10% heat inactivated fetal bovine serum (FBS). Cellswere infected at a seeding density of 3.5 million cells/mL in 500 cm³flasks at 5% v/v EP4 Bacman. Expression was carried out over 36 hrperiod at 37° C. with 5% CO₂. The cells were removed using PBS and acell scrapper. The cell culture was centrifuged at 2500 RPM for 10 minsat 4° C. The supernatant was then poured off and the pellet stored at−80° C. The pellet was defrosted and re-suspended in 15 mL ofhomogenising buffer (20 mM HEPES, 10 mM EDTA, pH 7.4). Then homogenisedin mechanical homogeniser (VMR) for 10 seconds. The membrane wascentrifuged in centrifuge tubes at 40,000 g for 15 mins at 4° C. Thesupernatant was poured away and re-suspended in 15 mL of homogenisingbuffer. Homogenised for 20 seconds. The membrane was centrifuged at40,000 g for 45 mins at 4° C. The membrane was re-suspended in 3 mL ofstorage buffer (20 mM HEPES, 0.1 mM EDTA, pH 7.4) mixing well. Theresulting membranes were then stored at −80° C.

cAMP Gs Functional Assay: cAMP production following EP4 receptoractivation was determined using the Homogeneous Time-ResolvedFluorescence (HTRF) cAMP dynamic-2 assay (Cisbio, France). HEK293 cellswere transfected using a 0.5% EP4 Bacman virus for 36 hours, beforedissociating the cells, and freezing at 150° C.

On the day of testing, increasing concentration of test compounds,alongside positive controls (1 uM ONO-AE3-208) and negative control(DMSO (Sigma-Aldrich, UK) were added to a ProxiPlate-384 Plus, White384-shallow well Mircoplate, (PerkinElmer, USA) using the ECHO dispense.

Cells were defrosted in a water bath and resuspended in DMEMsupplemented with 10% FBS before centrifuging at 1200 RPM for 5 mins toform a pellet. The pellet was resuspended in assay buffer (DMEM+0.5 mMIBMX (Tocris, Abingdon, UK, Catalog Number 2845)) to a 1×10⁶ cells/mL.Cell suspension, for a final assay concentration of 5000 cell/well wasadded using the multidrop to the pre-dispensed assay plate. The platewas then incubated at 37° C. for 30 mins, with 5% CO2. After incubation,EC₈₀ concentration (7 nM) of PGE₂ (EP4 agonist) was added to the plate.In parallel, a PGE₂ dose-response curve was dispense to a separateplate. Assay buffer was then dispensed on top. The cAMP production wasdetermined as manufacturer's instructions, before plates were read on aPheraStar fluorescence plate reader (BMG LabTech, Germany).

The pIC₅₀ was converted to a functional pKb value using a modified ChengPrussoff equation where K_(d)=agonist EC₅₀ and L_(hot)=agonist challengeconcentration;

${Ki} = \frac{{IC}50}{1 + \frac{\lbrack R\rbrack}{Kd}}$

TABLE 4 Human EP4 fpK_(b) values Human EP4 Example fpK_(b) 1 9.11 2 9.053 <7.17 4 <6.71 5 8.38 6 7.55 7 <6.71 8 8.06 9 <6.71 10 7.69 11 8.50 129.09 13 8.63 14 8.74 15 9.54 16 6.75 17 8.52 18 6.34 19 7.89 20 10.02 217.48 22 8.14 23 7.84 24 9.52 25 7.86 26 7.56 27 8.72 28 9.82 29 9.22 308.27 31 8.65 32 9.65 33 7.84 34 7.68 35 8.13 36 7.59 37 8.91 38 <5.33 399.64 40 8.78 41 <4.89 42 8.76 43 9.30 44 NT 45 8.00 46 8.14 47 7.19 486.85 49 8.64 50 <4.89 51 6.38 52 9.41 53 7.19 54 <4.89 55 9.32 56 8.1457 9.43 58 <4.89 59 8.01 60 8.72 61 9.47 62 9.40 63 7.59 64 7.32 65<6.68 66 7.46 67 9.24 68 9.25 69 9.02 70 8.16 71 9.43 72 9.23 73 6.74 749.35 75 7.16 76 7.48 77 7.56 78 <4.68 79 8.61 80 9.71 81 6.52 82 10.0683 9.73 84 7.95 85 10.26 86 9.35 87 <6.22 88 7.93 89 8.17 90 7.53 91 7.792 8.33 93 8.44 94 8.3 95 7.1 96 8.18 97 7.9 98 8.83 99 8.48 100 7.81101 9.07

1. A compound of Formula (1):

or a salt thereof, wherein; A is selected from the group consisting of:

X is an optionally substituted phenyl ring, an optionally substitutedpyridyl ring or an optionally substituted imidazopyridine ring system;R¹ and R² are independently H or a C₁₋₃ alkyl group which is optionallysubstituted with one or more fluorine atoms; or R¹ and R² are joined toform a 3-6 membered carbocyclic ring which is optionally substitutedwith one or more fluorine atoms; R³ is H, C₁₋₃ alkyl or F; R⁴ is H orC₁₋₃ alkyl; R⁸ is C₁₋₃ alkyl or a C₃₋₆ cycloalkyl ring; and either R¹⁰and R¹¹ are both methyl or R¹⁰ and R¹¹ are joined to form a cyclobutylring.
 2. The compound according to claim 1, which is a compound ofFormula (1a) or (1b):

or a salt thereof.
 3. The compound according to claim 1 wherein X is anoptionally substituted phenyl ring or an optionally substituted pyridylring.
 4. The compound according to claim 1, which is a compound ofFormula (2) or (2i):

or a salt thereof, wherein; Q, W and T are CH or N; Z and Y are C or N;where either one or none of Q, W, T, Y and Z is N, R⁵ is absent if Y isN and R⁶ is absent if Z is N; R⁵ and R⁶ are independently selected fromH, halo, CN, OH, SF₅, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, OR⁷ andSO₂R⁷, wherein the alkyl, cycloalkyl and alkoxy groups are optionallysubstituted with one or more fluorine atoms and any one atom of thealkyl or cycloalkyl group may be optionally replaced by a heteroatomselected from O, S and N; or R⁵ and R⁶ are joined to form a 5 or6-membered carbocyclic or heterocyclic ring which is optionallysubstituted with one or more fluorine atoms; and R⁷ is a C₁₋₆ alkylgroup which is optionally substituted with one or more fluorine atoms ora C₃₋₆ cycloalkyl group which is optionally substituted with one or morefluorine atoms.
 5. The compound according to claim 1, which is acompound of Formula (3) or (3i):

or a salt thereof; wherein Q, W and T are CH or N; Z and Y are C or N;where either one or none of Q, W, T, Y and Z is N, R⁵ is absent if Y isN and R⁶ is absent if Z is N; R⁵ and R⁶ are independently selected fromH, halo, CN, OH, SF₅, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, OR⁷ andSO₂R⁷, wherein the alkyl, cycloalkyl and alkoxy groups are optionallysubstituted with one or more fluorine atoms and any one atom of thealkyl or cycloalkyl group may be optionally replaced by a heteroatomselected from O, S and N; or R⁵ and R⁶ are joined to form a 5 or6-membered carbocyclic or heterocyclic ring which is optionallysubstituted with one or more fluorine atoms; and R⁷ is a C₁₋₆ alkylgroup which is optionally substituted with one or more fluorine atoms ora C₃₋₆ cycloalkyl group which is optionally substituted with one or morefluorine atoms.
 6. The compound according to claim 1, wherein R¹ and R²are both methyl, R¹ and R² are both H, R¹ and R² are joined to form acyclopropyl ring or R¹ is methyl and R² is H.
 7. The compound accordingto claim 6, wherein R¹ is methyl and R² is H.
 8. The compound accordingto claim 1, which is a compound of Formula (4) or (4i):

or a salt thereof; wherein Q, W and T are CH or N; Z and Y are C or N;where either one or none of Q, W, T, Y and Z is N, R⁵ is absent if Y isN and R⁶ is absent if Z is N; R⁵ and R⁶ are independently selected fromH, halo, CN, OH, SF₅, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, OR⁷ andSO₂R⁷, wherein the alkyl, cycloalkyl and alkoxy groups are optionallysubstituted with one or more fluorine atoms and any one atom of thealkyl or cycloalkyl group may be optionally replaced by a heteroatomselected from O, S and N; or R⁵ and R⁶ are joined to form a 5 or6-membered carbocyclic or heterocyclic ring which is optionallysubstituted with one or more fluorine atoms; and R⁷ is a C₁₋₆ alkylgroup which is optionally substituted with one or more fluorine atoms ora C₃₋₆ cycloalkyl group which is optionally substituted with one or morefluorine atoms.
 9. The compound according to claim 1, which is acompound of Formula (5) or (5i):

or a salt thereof wherein: Q, W and T are CH or N; Z and Y are C or N;where either one or none of Q, W, T, Y and Z is N, R⁵ is absent if Y isN and R⁶ is absent if Z is N; R⁵ and R⁶ are independently selected fromH, halo, CN, OH, SF₅, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, OR⁷ andSO₂R⁷, wherein the alkyl, cycloalkyl and alkoxy groups are optionallysubstituted with one or more fluorine atoms and any one atom of thealkyl or cycloalkyl group may be optionally replaced by a heteroatomselected from O, S and N; or R⁵ and R⁶ are joined to form a 5 or6-membered carbocyclic or heterocyclic ring which is optionallysubstituted with one or more fluorine atoms; and R⁷ is a C₁₋₆ alkylgroup which is optionally substituted with one or more fluorine atoms ora C₃₋₆ cycloalkyl group which is optionally substituted with one or morefluorine atoms.
 10. The compound according to claim 4, wherein W, Q andT are CH and Z and Y are C.
 11. The compound according to claim 1 whichis a compound of Formula (6) or (6i):

or a salt thereof; wherein R⁵ and R⁶ are independently selected from H,halo, CN, OH, SFs, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, OR⁷ andSO₂R⁷, wherein the alkyl, cycloalkyl and alkoxy groups are optionallysubstituted with one or more fluorine atoms and any one atom of thealkyl or cycloalkyl group may be optionally replaced by a heteroatomselected from O, S and N; or R⁵ and R⁶ are joined to form a 5 or6-membered carbocyclic or heterocyclic ring which is optionallysubstituted with one or more fluorine atoms; and R⁷ is a C₁₋₆ alkylgroup which is optionally substituted with one or more fluorine atoms ora C₃₋₆ cycloalkyl group which is optionally substituted with one or morefluorine atoms.
 12. The compound according to claim 1, wherein A isCO₂H, CONHSO₂Me or a tetrazole ring.
 13. The compound according to claim12, wherein A is CO₂H.
 14. The compound according to claim 1, wherein R³is H or methyl.
 15. The compound according to claim 14, wherein R³ is H.16. The compound according to claim 1, wherein R⁴ is H or methyl. 17.The compound according to claim 16, wherein R⁴ is H.
 18. The compoundaccording to claim 4, wherein R⁵ and R⁶ are independently selected fromH, Cl, F, CN, OH, SO₂Me, SO₂Et, SO₂-cyclopropyl, SF₅, CF₃, CF₂H, OMeOCF₃, OCF₂H, CH₂OH, CH₂OMe, cyclopropyl and oxetanyl.
 19. The compoundaccording to claim 4, wherein R⁵ is H.
 20. The compound according toclaim 19, wherein R⁶ is CF₃ or F.
 21. The compound according to claim 4,wherein R⁵ and R⁶ are joined to form a fused imidazole ring or a fuseddioxolane ring which is optionally substituted with one or two fluorineatoms.
 22. The compound according to claim 1 which is selected from thegroup consisting of:

or a salt thereof.
 23. The compound according to claim 1 having EP4receptor antagonist activity.
 24. A pharmaceutical compositioncomprising a compound as defined in claim 1 and a pharmaceuticallyacceptable excipient.
 25. A method for treating, preventing,ameliorating, controlling or reducing the risk of a disorder associatedwith EP₄ receptors comprising adminisering to a subject in need thereofa compound according to claim
 1. 26. The method of claim 25, wherein thedisorder associated with EP₄ receptors is selected from the groupconsisting of: Abdominal aortic aneurysm (AAA), Ankylosing spondylitis(AS), Alzheimer's disease, Atherosclerosis, Cancer including epithelialcancers (GBD neoplasm categories of colon and rectum, lip and oralcavity, nasopharynx, other pharynx, gallbladder and biliary tract,pancreatic, non-melanoma skin, ovarian, testicular, kidney, bladder,thyroid, mesothelioma, esophageal, stomach, liver, larynx, tracheal,bronchus and lung, breast, cervical, uterine, prostate), Diabeticnephropathy, Endometriosis, Inflammatory bowel disease, Migraine,Multiple sclerosis (MS), Osteoarthritis (OA) and Rheumatoid arthritis.